Multiple sclerosis (MS) is the most common chronic inflammatory disease of the CNS and the major cause of neurological disability in young adults in developed countires. MS is an autoimmune human disease. The diease typically hits people ages 20-40 and is more common in women. MS is a leading cause of nuerologic disability that affects about 400,000 people in the US and 2.5 million worldwide (Ruff, “Identification of peptide mimotope ligands for natalizumab” Scientific Reports (2018) 8, 14473). 

Relapsing-remitting multiple sclerosis (RRMS). Multiple sclerosis is a disease in which the immune system (the body’s defences) attacks and damages the protective insulation around the nerves and the nerves themselves in the brain and spinal cord. In RRMS, the patient has flare-ups (relapses) followed by periods with milder or no symptoms (remission).

Risk factors

MS affects about one million people worldwide with 350,000 cases in North America alone. It ranks as a major cause of nervous-system disability in young adults between the ages of 15 and 45 years. Women are affected two times more frequently than men.

Since the 1960s, a possible linke between MS and mercury exposure from amalgam used to fill dental caries has been explored.

Pathology

MS is usually a sporadic disease and is characterized as a variably progressive human disease of the nervous system in which patchy degenerative and inflammatory changes occur within the brain and spinal cord. MS is a chronic inflammatory disease characterized by lymphocyte infiltration and inflammation of the central nervous systen (CNS) white matter. T cells recognizing myelin protein peptides are likely involved in the pathogenesis of the disease. Myelin is a fatty substance which covers the axons of nerve cells and is important for proper nerve conduction. The disease often beings in young adulthood with recurrent inflammatory attacks against the white matter of the brain, producing a myriad of neurological impairments, including blindness, loss of senstation, lack of coordination, bowel and bladder incontinence and diffculty walking.

MS is an autoimmune disease that is characterized by inflammation in parts of the central nervous system, leading to the loss of the myelin sheathing around axonal nuerons (demyelination), loss of axons, and the eventual death of neurons, oligodendrocytes and glial cells. (US Patent No: 8,399,514)

Abnormalities and Causes of MS

Inflammation and autoimmunity: In MS, certain T cells trigger inflammatory processes when they encounter myelin, stimulating other immune cells and soluble factors like cytokines and antibodies. MS is characterized by loss of the myelin sheath around axons, activation of complement, activation of microglia/macrophages, invasion of leukocytes, astrongliosis and finally destruction of oligodendroglial cells and axonal process (Schwab, Exp. Neurology, 174, 2002, 81-89). The inflammatory processes triggered by the T cells creates leaks in the blood brain barrier which causes swelling, activation of macrophages and more activation of cytokines and destructive proteins like matrix metalloproteinases. The final result is demyelination or destruction of myelin.

The hallmark pathology in MS is the plaque- an area of myelin that has been denuded by inflammation and subsequent scarring by non-neural cells in the brain, including bone marrow derived microglia and brain derived star shaped astroglia. The cause of MS is enigmatic, although most investigators believe that immune attack against white matter is paramount, with the resulting degeneration of axons and nyelin being secondary to this inflammatory process.

T Regulatory Cell Dysfuction: There are few reports on functional analysis of CD4+CD25high cells isolated form patients with autoimmune disease. One reports finds no difference in the frequency of these cells between patients and healthy controls but T-reg cells derived form patients as compared to healthy controls did exhibit significantly less suppressive function.

Th1/Th2 Imbalance: MS is believed to be an autoimmune disease in which Th1 immune responses predominant. This response is associated with an increased production of IFNy and IL12 produced by T cells and by cells of the monocyte lineage. An increased expression of costimulatory molecules by T cells and APCs

Experimental Models

Experimental autoimmune encephalomyelitis (EAE), an inflammatory CNS demyelinating disorder which serves as the prime animal model for MS can be induced in a number of species by immunization with myelin components or injection of autoimmune T lymphocytes.

Treatment

Antibodies:

–Anti-Integrins:

—-Natalizumab (marketed as Tysabri): is the top selling biologic drug indicated for MS. It is highly effective in treating MS patientsand was shown to reduce sustained physical disability by 52% relative to placebo. Natalizumab is a huanized recombinant IgG4 mAb that targets the alpah4 chain of alpha4beta1 integrin (also known as very late activation antigen 4; VLA-4) and alpah4beta7 integrin (LPAM-1). It is thought to function by blocking migration of immune cells across the blood-brain barrier into the CNS thus suppressing inflammation in patients with relapsing-remitting MS. (Ruff, “Identification of peptide mimotope ligands for natalizumab” Scientific Reports (2018) 8, 14473). 

The immunosuppressive activity of natalizumab has been associated with opportunistic infection by John Cunningham (JC) virus which may lead to progressive multifocal leukoencephalopathy (PML), a serious and often fatal opportunistic brain infection. (Ruff, “Identification of peptide mimotope ligands for natalizumab” Scientific Reports (2018) 8, 14473). 

 Inteferons: Three treatment for MS are interferons: Interferon beta-1a (Avonex and Rebif) or beta-1b (Betaseron). Part of there mechanism may be to reduce MO CD86 and CD40L expression as well as IL-12 secretion. IFN-B induces IL-10 secretion and suppresses IFN-y-inducible MHC class II up regulation an APC.

Glatiramer acetate (COPXONE): A fourth approved medication is glatiramer acetate (Copaxone), a mixture of polypeptides which may protect important meylin proteins by substituting itself as the target of immune system attack. Yeda Research Development Co is the assignee of US Patent Nos: 8,232,250, 8,399,413, 8,969,302 and 9,155,776 which describe and claim COPAXONE 40 mg/mL for treating relapsing remitting multiple sclerosis (“RRMS). The active ingredient is glatiramer acetate (“GA”), a synthetic mixture of polypeptides. The treatment consists of inection of 40 mg of GA three times a week. These patents were latter found invalid for obviousness (see Tevan Pharmaceuticals v. Sandoz Inc, Fed. Cir, 2017). 

Mitoxantrone: A fifth medication, mitoxantrone is effective but is limited by cardiac toxicity. All of the medications cited require frequent injections and are expensive.

Ocrelizumab: The newest and most promising treatment is a drug called ocrelizumab manufactured by Roche (RHHBY) which blocks B cells The FDA has approved ocrelizumab for treatment of primary progressive MS, making it the first drg ever approved for the most aggressive form of the disease. The drug was originally approved for non-Hodgkin lymphoma. In one study, the drug cut annualized repalse rate almost in half compared with a commonly used treatment Rebif. The formation of new lesions in the brain and spinal cord, the key marker of inflammation was reduced by more than 94% compared to patients on Rebif.

Corticosteroid: MS patients are usually given high doses of intravenous corticosteroids, such as methylprednisolone to end the attack sooner. This corticosteroid treatment however does not appear to have a significant impact on long term recovery. During symptomatic attacks, patients may be hospitalized.

4-AP (AKA “dalfampridine” and “fampridine”) belong to a class of compounds that function as potassium channel blockers and have been found to slow the potassium flow in nerve impulse transmission and by doing so help restore conduction in blocked and demyelinated nevers. MS caues demyelnations (loss of myelin) of ncerves in the CNS and results in a wide vareity of symptoms, including walking impariment, tingling or pain, brain scarring, cognitive changes, visual impairments and fatiuge. The FDA has approved Amprya, a 10 milligram 4-AP sustained release tablet for twice daily oral administration. . 

Bone marrow transplant and total lymphoid irradiation have been studied and are currently reserved for the most dire cases.

Dimethyl fumarate (DMF, Tecfidera) was approved by the US FDA in March 2013 as an oral disease modifying treatment for relapsing forms of MS. Combined data from a Phase II study and two Phase III trials showed that DMF reduces relapses, disability progression, MRI lesion activity.

The exact mechanism of action of DMF is not known but may include direct inhibition of proinflammatory pathways and effects on dendritic cell differentiation. DMF may also act through the nuclear factor (erythroid-derived 2) like 2 (Nrf2) antioxidant response pathway.

Sphingosine-1-phosphate receptor inhibitors: Zeposia by Bristol Myers contains an active substance, ozanimod, which blocks the action of sphingosine-1-phosphate receptors on lymphocytes (cells of the immune system that can attack the body’s own tissues in diseases such as multiple sclerosis or ulcerative colitis). By attaching to these receptors, ozanimod stops lymphocytes from travelling from the lymph nodes towards the brain, spinal cord or intestine, thus limiting the damage they cause in multiple sclerosis and ulcerative colitis.

Natural products: Among natural products, a recent study found that women who took vitamin D supplments were 40% less likely to develop MS than women who did not take supplements. There were, however, some controversy regarding whether or not the beneficial effects were due to vitamin D or multivitamin supplments including vitamin E and various B vitamins, which may also exert a protective effect.

Landscape

US Patents for transgenic mice models: U.S. Patent 5,387,742 U.S. Patent No. 5,602,299

NIH Neurosciences Blueprint. Alzorum 

Diagnostic Tests: Quest  (The calculated ratio of Beta-amyloid 40 and Beta-amyloid 42)

Introduction: 

Alzheimer’s disease (AD)  is the most common neurodegenerative disorder and the main cuase of dementia. (Rhinn, “Shifting paradigms: The central role of microglia in Alzheimer’s disease” Neurobiology of Disease 143 (2020)). The Alzheier’s treatment space is projected to be wroth 15.5 billion by 2031, accordig to hHealthcareAnalyst. 

AD is a progressive disease resulting in senile dementia. It is a progressive disease of the human central nervous system and manifested by dementia in the elderly, by disorientation, loss of memory, diffficulty with language, calculation, or visual spatial skills and by psychiatric manifestations. It is estimated that healthcare spending on Alzheimer’s disease and related age related dementials in 2012 is 200 billion in the US alone. 

AD falls into 2 categories: late onset, which occurs in old age (65+ years) and early onset which develops before the senile period (between 35-60). In both types, the pathology is the same but the abnormalities tend to be more severe and widespread in cases beginning in early age.

Pathology and Biomarkers: 

Alzheimer’s disease (AD) is a progressive neurodegenerative disease affecting nerve cells located within higher cortical centers that ultimately results in impaired cogntion, including a gradual decline in memory, judgment, and communication. AD is characterized by at least 2 types of lesions in the brain, neurofibrillary tangles and senile plaques. The principal constituent of the plaques is a peptide called “Abeta or beta-amyloid peptide”. 

AD shares features with otehr neurodegenerative disorders such as cerebral atrophy, neuron and synapse loss, accumulation of intracellular protein aggregates in neurons, and glial activation, but also other features more specific to AD such as the accumulation of extracellular proteins aggregates, called amyloid plaques. (Rhinn, “Shifting paradigms: The central role of microglia in Alzheimer’s disease” Neurobiology of Disease 143 (2020))

AD is characterized by the presence within the brain of amyloid fibril containing neuritic plaques comprised of proteolytically derived 40-42 resiude fragments of the amyloid precursor protein. Historially, Abeta fibrils have been deemed primarily responsible for neuronal dysfunction and death; however, more recent evidence indicates that oligomers, which includes soluble cross-lined beta-amyloid protein species (CAPS), are the most pathogenic Abeta conformers. (Nuallain, Biochemistry 2008, 47, 12254-12256). 

AD is characterized by age-assocaited progressive memory decline. Two hallmarks of AD are amyloid beta and tau. 

Amyloid Peptides: (e.g., Amyloid beta protein): 

Neuropathological and genetic data stronly supports a primary role for amyloid peptides, particulalry amyloid beta protein, which accumulate as seile plaques in brain parenchyma, in the pathogenesis of AD. The presence of circulating Abeta like antibodies in the peripheral blood of AD pateints is known (Mruthinti, Neurobiology of Aging 25 (2004) 1023-1032).

Abeta peptide is a 4 kDa internal fragment of 39-43 amino acids of a larger transmembrane glycoprotein named amyloid precursor protein (APP). As a result of proteolytic processing of APP by different secretase enzymes, Abeta is primarily found in both a short form, 40 amino acids in lenght, and a long form, rangering from 42-43 amino acids in lenght. Several mutations within the APP protein have been correlated with the presence of AD.

The amyloid hypothesis holds that the accumulation of amyloid-beta (Aβ) is responsible for Alzheimer’s disease. Proponents of this theory believe that when amyloid beta clumps together to form deposits in the brain, it triggers neurodegenerative processes that lead to the loss of memory and cognitive abilities that characterize the disorder. Despite the recent FDA approval of anti-amyloid antibodies for Alzheimer’s disease and new investment in the space, skepticism remains about the value of these first disease-modifying drugs and the validity of the amyloid hypothesis. (“Amyloid Hypothesis in Doubt as Newly Approved Drugs Hit Hurdles” Biospace, 2024)

While the exact role of Aβ in Alzheimer’s is up for debate, anti-amyloid antibodies without a doubt have some effect on the disease process. Legembi (see below) for example educed clinical decline by 27% compared to placebo based on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) assessment in patients with mild-to-moderate Alzheimer’s, and Kisunla (see bloew) reduced decline by 29% on the CDR-SB. But  “The effect is less than Aricept [an earlier Alzheimer’s drug], and yet they’re moving forward. If the theory was correct, if you remove the amyloid, some patients should get better. Thus while amyloid is “important” to the Alzheimer’s disease process, it is not the driver. Rather, amyloid accumulation may be a response to neural damage, given that antioxidant qualities found in amyloid-beta. With the currently approved anti-amyloid antibodies, the amount of drug that gets into your brain is also about 1%, which is not a very efficient way of treating Alzheimer’s disease. Several companies—including Denali Therapeutics, Voyager Therapeutics and Aliada—are developing technologies to improve on that number. Roche’s anti-amyloid antibody trontinemab is an example of a therapy attempting to get the antibody across the BBB. Developed using the company’s proprietary Brainshuttle platform, trontinemab can cross the BBB and achieve higher levels of brain exposure and broader distribution across the central nervous system. at this point, that Alzheimer’s will have to be treated with multiple drugs attacking multiple mechanisms that are related to the biology of aging. (“Amyloid Hypothesis in Doubt as Newly Approved Drugs Hit Hurdles” Biospace, 2024)

Amyloid Beta Oligomers and Fibrils:  Amyloid beta fibrils are been found primarily responsible for neuronal dysfunction and death. In addition, oligomers that include soluble cross-linked beta amyloid protein species (CAPS) have also been found detrimental. (Nuallain, Biochemistry, 2008, 47, pp. 12254-12256). 

Receptor for AGEs (RAGE): occur in AD brain within hippocampal pyramidal cells, cortical neurons, glial cells and white matter. Some evidence exists to suggest that RAGE permits the accumulation, supports the aggregate of Abeta, resulting in inflammation and cytotoxicity in neuronal cells. AD individuals are also known to express high levels of anti-RAGE IgGs as shown from purificaiton of RAGE from plasma samples. (Mruthinti, Neurobiology of Aging 25 (2004) 1023-1032).

Tau:

–hyperphosphorylation

Tau is a microtubule (MT) associated protein particularly abundant in neurons, where it mostly localizes to axonal regions. It regulates MT stability and the maintenance of axonal transport. Under physiological conditions, tau binding to MTs is coordinated by phosphorylation, requiring a precise interplay of a multitude of kinases and phosphatases. In pathological conditions such as AD and related neurodegeenrative disorders called tauopathies, increased phosphorylation of tau is associated with a decrease in its binding to microtubules. This in turn results in tau misolding and self-aggregation, eventually leading to the accumulation of insoluble, paired helical filaments and other filamentous structures. Thai pathological tau aggregation is a shared molecular mechanism in more than 20 neurodegenerative conditions, including AD. While tau in the noraml brain contains 2-3 phosporylated residues per tau molecule, it is estimated to be about 3-fold hyper-phosphorylated in AD brain. Accumulating data indicates that phosphorylation alone is not sufficient for aggregation and might even serve a protective role. Several other post-translational modifications such as acetylation, ubiquitination, methylation and glycosylation among others appear to play regulatory roles as well with respect to rates of tau clearance and aggregation and thus contribue to tau pathology. (Steen, WO 2017/053739). 

—-Specific patterns of hyperphosphorylation

——T205 and T181:

Barthelemy (US 17/015,985, published as US 2020/0400689; see also US Patent applicaiton No: 17/368403 published as US 2021/0341495) discloses a method for selecting a therapeutic agent that prevents amyloid deposit and reduces amyloid plaque load or targets neurofibrillary tangles based on a specific tau phosphorylation pattern. In one embodiment, a therapeutic agent is administered when the isolated tau sample from a subject contains tau phosphorylation at T181 or p217 at about 1.5 dstand deviations above and tauphosphorylation at T205 that is below about 1.5 standard deviations. 

Russel “Comprehensive quantitative profiling of Tau and phosphorylated Tau peptides in cerebrospinal fluid by mass spectrometry provides new biomarker candidates” J of Alzheimer’s disease, 55 (2017) 303-313) disclsoes that aberrant tau phosphorylation is a hallmark in AD and that cerebrospinal fluid (CSF) levels of total tau and tau phosphorylated at threonine resiude 181 (pThr181) are established ore biomarkers for AD. 

Vasan (US 2008/0220449) discloses diagnosing, stratifying and monitoring the progression or regression of AD which includes detecting in a sample a level of at least phosphorylated tau pT217, soluble tau oligomer, tau-amyloid-beta 1-42 complex and a combination thereof and comparing the level form the sample to a reference level. Vasan disclsoes that other biomarkers for AD utilize the ratio of p-tau to Abeta1-42 as a senstive marker for discriminating patients with AD form healthy controls and that changes in lvels of tau and Abeta-142, pTau 181 over teh baseline were much higher between groups than in the same groups during the progression of the disease. 

——Ser202/Thr205/Ser208: 

Despres (PNAS, “Identificaiton of the Tau phosphorylation pattern that drives its aggregation” 2017, 114(34)) discloses using in vitro kinase assays combeind with NMR spefctroscopy to show that the combined phosphorylation at the Ser202/Thr205/Ser208 sites, together with absence of phosphorylation at the Ser262 sites, yeild a Tau sample that readily forms fibers, as observed by thioflavin T fluorescence and electron microscopy. 

–Tau kinases and their inhibitors

Multiple protein kinases such as GSK3 (a serine/threonine kinase), CDK5, Akt and PKA can phosphorylate tau. (Xu, US 2009/0233993). 

The thousand-and-one amino acid kinases (TAOKs) 1 and 2 phosphorylate tau on more than 40 residues in vitro.. TAOKs are phosphorylated and active in AD brains actions displaying tau patholoy and active TAOKs co-localise with both pre-tange

le and tangle structures. TAOK inhibitors can reduce tau phosphorylation on T123 and T427 and also on additional pathological sites. Such TAOK inhibitors also have been shown to decrease tau phosphorylation in differentiated primary cortical neurons. ((Giacomini, Acta Neuropathologica Communications (2018) 6: 37). 

Reagan (US 2009/0104628) discloses a method for measuring phosphorylation of proteins such as tau at specific serine, threonine or tyrosine residues by subjecting the protein to a reaction mixture that includes a phosphokinase which allows the creation of a phosoryalted form of the protein which is then contacted with an antibody specific for the phosphorylation site(s). 

Role of Microglia:

Genome-Wide Associattion studies from large European and American consortia identified common genetic polymorphisms at loci harboring gnes with microglia-specific epxrewssion pattern in the CNS, such as ABC7, CD33 and members of the MS4A genes cluster as genetic determinatns of AD risk. The identificaiton of TREM2 R47H and its strong effect size on AD risk association marked a turning point in establshing microglia as a central play in AD pathogenesis. (Rhinn, “Shifting paradigms: The central role of microglia in Alzheimer’s disease” Neurobiology of Disease 143 (2020))

–APOE:

While APOE is predominantly expressed by astrocytes in the healthy brain, it is dramatically upregulated by microglia upon inflammation or injury. Genome-Wide Associattion studies from large European and American consortia identified common genetic polymorphisms at loci harboring gnes with microglia-specific epxrewssion pattern in the CNS, such as ABC7, CD33 and members of the MS4A genes cluster as genetic determinatns of AD risk. (Rhinn, “Shifting paradigms: The central role of microglia in Alzheimer’s disease” Neurobiology of Disease 143 (2020))

–TREM2:

TREM2 is an imune receptor exprewssed in the myeloid lineage, priimarily tissue resident macrophages, including microglia and osteoclasts. TREM2 is a cell surface receptor containing one immunoglobulin domain with no intracellular signaling motifes. Instead TREM2 binds sto the adaptor protin DAP12/TYROBP and to a less extent to DAP10. DAP12 has an immunoreceptor tyrosin-based activating motif (ITAM) that acts as a signal transducer and DAP12 is also essential to traffice TREM2 to the cell surface. A vareity of tREM2 lgiands have been identified, including phospholipids, bacterail surface antigens as well as the AD risk genes APOE and APOJ/CLU. Ligand binding to tREM2 clusters the receptor, which induces DAP12 phosphorylation at the ITAM, recruitment and phosphorylation of SYK and subsequent activation of a downstream signaling cascade that has primarily been studied in osteoclasts, DCs and somewhat in microglia. TREM2 ligation idncues recruitment of SHIP1 and PI3K, which signals through mTOR, as well as activaiton and nuclear transport of beta-cartenin and rapid calcium influx and phosphyrlation of ERK1/2 Human genetics has shown a central role for microglia in AD etiology. The identification of TREM2 as a genetic risk factor marked a turning point in AD genetics. TREM2 R47H was a rare nonsynonymous coding mutation in a known gene, known to be exclusively expressed in microglia in the brain. Mutations in TREM2 and DAP12/TYROBP, its binding partner, were known to cause Nasu-Hakola disease, which is characterized by early onset dementia (among other patholgies in the periphery) and the strong effect size of the mutation that tripled diease risk was proof of its importance.  The most prevalent TREM2 mutation associated with AD is the R47H missense mutation. While this variant does not appear to modulate TREM2 expression, maturation or localization, it does reduce ligand binding and ligand mediated TREM2 signaling, suggesting that it is a hypomorphic mutation. Furthermore, people carrying two copies of different TREM2 hypomorphic or loss of funciton mutations develop early onset neurodegenerative diseases, such as leukodystrophy, called Nasu-Hakola Disease or Frontotemperoal dementia. (Rhinn, “Shifting paradigms: The central role of microglia in Alzheimer’s disease” Neurobiology of Disease 143 (2020))

–CD33:

CD33 is a member of the Siglec family of sialic acid bidning receptors. It carries an immunoreceptor tyrosin-based inhibitory motif (ITIM). Siglects generally funciton by engaging specific sialidated glycans on either neighboring cells (trans) or the same cell (cis ) an dwhen engaged, they block the activity of ITAM carrying receptors by recruiting SH2 domain phosphatases that induce dephosphorylation of SYK. CD33 was identified as an AD risk gene by GWAS analysis. SNPs that reduce CD33 expression are assocaited witih a reduced AD risk and reduced CD33 expression correlates with reduced Abeta pathology in human AD patient brains. Later on, the funcitonal SNP was identified to casue alternative splicing of CD33 that reoves its ligand binding domain and reduces cell surface expression. Genome-Wide Associattion studies from large European and American consortia identified common genetic polymorphisms at loci harboring gnes with microglia-specific epxrewssion pattern in the CNS, such as ABC7, CD33 and members of the MS4A genes cluster as genetic determinatns of AD risk. (Rhinn, “Shifting paradigms: The central role of microglia in Alzheimer’s disease” Neurobiology of Disease 143 (2020))

Diagnostics/Detection:

–Amyloid PET imagaging:

Amyloid PET is a well established biomarker that is widely used in clincial trails and observational studies to detmerine brain amyloid plaque burden. (Bateman, “Validation of plasma amyloid-ß 42/40 for detecting Alzheimer Disease amyloid plaques” American Academy of Neurology, 2021).

–Aβ42/Aβ40: 

Plasma Aβ42/Aβ40 is a robust measure for detecting amyloid plaques and can be utilized to aid in the diagnosis of AD and identify those at risk for future dementia due to AD. Thea ssay has been developed commercially (PrecivityAD by C2N Diagnostics) and is being used by physicains in the clinic to detect amyloid plaques and assit in diagnosis of AD dementia.  (Bateman, “Validation of plasma amyloid-ß 42/40 for detecting Alzheimer Disease amyloid plaques” American Academy of Neurology, 2021). 

—-The AD-Detect Test for Alzheimer’s Disease (Quest Diagnostics): is a blood test for Alzheimer’s disease, measures A-beta 42 and A-beta 40 biomarkers (a biological marker of a molecule found in the body that may be used in evaluating a disease state) in the blood and provides the A-beta 42/40 ratio. The ratio between these two molecular biomarkers may help to detect risk of Alzheimer’s disease in an individual. 

Treatment: 

The FDA has approved two types of medications for the maangement of Alzheimer’s disease: cholinesterase inhibitors and the NMDA-type glutamate receptor inhibitor memantine. These therapies serve to alleviate cognitive symptoms such as memory loss, confusion and loss of critical thinking abilities in subjects diagnosed with age related dementia. In addiition to these approved therapies, several sutdies have suggested that poole intravenous immunoglbulin is effective in slowing the progression fo symptoms. (Hofbauer, US2014/0271669). 

Under certain circumstances, immune cells in the brain, known as microglia, promote the inflammatory and destructive process that can lead to Alzheimer’s disease. It has been reported that once a specific molecule on the surface of microglia, CD40, get activated by its partner, CD40 ligand, the scene is set for microglial injury to the main cells in the brain; the neurons.

Researchers are currently administering anti-CD40 ligand antibody to mice so as to develop symptoms similar to Alzheimer’s disease. The mice can then be immunized with an investigational anti-Alzheimer’s vacine shown to remove beta amyloid plaques that accumulate in the brain, thereby leading to nerve damage and memory loss (Morgan).

Chlinesterase inhibitors: include Aricept (donepezil), Exelon (rivastigmine), Razadyn (galantamine) and Cognek (tacrine)

NMDA-type glutamate receptor inhibitor memantine:

Anti-amyloid Beta Antibodies:

Treatments that focus on amyloid-beta plaque, which is tightly linked to AD include ad

–Aducanumab and BAN2401: (Biogen) After poor results in 2019, the company presented positive date from a phase-3 trial. The durg robustly removes amyloid, possible clears tau tangles and at sustained high doses may modestly slow decline.

–Bepranemab (UCB0107): Roche’s Genetech had a collaboration in 2020 with UCB to develop an anti-tau antibody and gave over 120 million upfront to UCB with the Belgia company eligible for 2 billion based on certain regulatory approvals. However, Roche terinated the partnership.  

–Crenezumab: Roche terminated its collaboration with AC Immune over the anti-amyloid beta antibody crenezumab  beause it failed Phase II and III clinical trails in 2019 and 2022. 

–Gantenerumab: failed wo phase III studies in November 2022. 

Leqembi (Lecanemab): targets Alzheimer’s disease protein that are thought to be the most toxic to brain cells. It reduces clumps of amyloid-beta proteins, which play a key role in Alzheimer’s disease. However, lecanemab is not helpful for people with full cognitive function or later stages of Alzheimer’s. Lecanemab is manufactured by the Japanese pharmaceutical company Eisai and its U.S. partner Biogen. The drug is not a miracle drug in that it does not stop, reverse or cure the disorder. It can slwo mental decline by 5 months over an 1ucanumab and lecanemab, which were approved in 2021 and 2023, respetively, for mild cognitive impairment adn early AD. These treatments are beleived to reduce plaque in the brain, but they do not bring about cures. There are cases in which the plaque has been completely removed, but the people are still declining, so additional therapeis are needed. 8 month treatment period. But it comes with side effects including the risk of brain swelling and blooding. Despite all these drawbacks, it represetns a breakthrough. 

Kisunla (donanemab-azbt) (Ili Lilly): is a once monthly injection greatment indicated for adults with early symptomatic Alzheimer’s dieaes (AD) including mild cognitve impariment (MCI) or mild dementia stage of disease with confirm amyloid pathology. Kisunla is the first amyloid plaque targeting therapy with evidence to support stopping therapy when amyloid plaques are removed, which according to Lilly can reduce both the number of infusions needed as well as the treatment cost. The FDA based its approval of Kisunla on positive data form Phase III TRAILBLAZER-ALZ 2 trail (NCT04437511), in which people elast advanced in the disease showed the strongest results 18 months after receiving the drug. Treatment with Kisunla significantly slowed clinical decline in two groups: pateints with low to medium levels of tau protein adn patients mirroring the overall popuation, which also inluded participants with high tau levels. Lilly has set a list price of of about 32,000 for a year of treatment which is about 21% above the $26,500 annual list price for Leqembi, an Alzhiemr’s treatment marketed by Isai and Biogen. 

Gantenerumab: (Chugai Pharmaceutical Co., Ltd., Hoffmann-LaRoche): is a fully human IgG1 antibody designed to bind with subnanomlar affnity to a conformational epitope on amyloid-beta fibrils. It encompasses both N-temrinal and central amino acids of amyloid-beta. The therapetuic rationale is that it acts to disassemble and degrade amyloid plaques by recuiting microglia and activating phagocytosis. Gantenerumab preferentially interacts with aggregated brain amyloidbeta, both parenchymal and vascular. 

–Patents:

Du (US 2002/0009445) discloses infusion of human IgG anti-amyloid beta antibodies for treatment of AD patients. The Anti-amyloid beta antibodies were recovered form a body fluid such as plasma using amyloid beta affinity chromatography. 

Hyman (Ann Neurol, 2001, 49, pp. 808-810) discloses analysis of the plasma of 365 individuals for the presence of antibodies to amyloid-beta. There were detectable but very low levels of anti-amyloid-beta antibodies in just over 50% of all samples and modest levels in under 5% of all samples. However, neither the presence nor the level of anti-amyloid-beta antibodies correlated with the likelihood of developing demential or with plasma levels of amyloid-beta peptide. 

Math (Neuromolecualr Med. 2003; 3(1): 29-39) disclose that AD patietns exhibit an enhanced immune response to Abeta adn that, contrary to expectation, Abeta antibodies enhance the neurotoxic activity of the peptide. Serum titers to Abeta were significantly elevated in AD patients and Abeta antibodies were found in association with amyloid plques in their brains, but there was no evidence of cell mediated immune responses to Abeta in the patents. 

–IVIG administration:

It has been shown that antibodies against beta-amyloid (Abeta) are present in human immunoglobuilin preprations (IVIgG). Commerically available IVIG preparations contain IgGs that specifically recognize epitopes of varous conformers of amyloid beta (e.g.,  amyloid beta monomers, amyloid beta fibrils and cross-linked amyloid beta protein species CAPS). Form example, GAMMAGARD LIQUID (10% immune globulin infusion (humna) contain 0.1% anti-amyloid beta fibril IgG, 0.04% anti-CAPS IgG and 0.02% anti-amyloid beta monomer IgG. 

Dodel (J Nuerol Nuerosurg Psychiatry, 2004, 75(10) 1472-4) reports that in a study of 5 patients with AD who received monthly IVIgG over 6 month period, total Abeta levels in the CSF decreased by 30.1% and imporvement was deetected using an ADAS-cog.

Eggenburg (US 15/385721, published as US 2017/0218051) discloses a high titer anti-amyloid beta pooled immunogloublin G composiiton that contains at least 0.1 antiamyloid beta IgG. In one embodiment, the composition contains at least 1% anti-amyloid beta fibril IgG, at least 0.4% anti-amyloid beta oligomer immunogloublin G, at least 0.2% anti-amyloid beta monomer IgG and a pharmaceutically acceptable stablizing agent. In some embodiments, the composition further includes anti-RAGE IgGor anti-alpha-synuclein IgG. Methods for administering a therapeutically effective amoun of the IgG compostions for the treatment of a disorder such as Alzheimer’s disease are also disclosed. 

Puli (J Neuroinflammation, 2012, 9:105) disclose that treatment of transgenic and WT mice with hIVIG provided no reduction in amyloid beta pathology but rather increased soluble levels of AB40 adn AB42. 

Relkin (Nuerobiology of Aging 30 (2009) 1728-1736) discloses that antibodies against beta-amyloid which are contained in IVIg which was infused into AD patients decreased cerebrospinal fluid AB and also led to improvement indicators such as mini-mental state scores. 

Anti-Tau antiodies: 

–Semorinemab: Roche ended its partnership with AC Immune regarding its anti-tau antibody semorinemab becaseu semorinemab failed to hit its priary endpoint, as well as two secondary endpoints. 

Peptides/small molecuels:

–Companies: NervGen

–Protein tyrosine Phosphatase signma (PTPsigma): (NervGen): Their lead product NVG-291 provides a potential therapy for Alzehimer’s. The peptide binds preferentially to the PTPsignma receptor and effectively present inhibition from happening. Scar romation is a would healing process that takes place thorugh the body, including the nervous system. After an injury, more chonditin sulfate proteolycans (CSPs) is produced in its location. These sticky proteins act as a potent barrier to protect a wound and creat a wall to constrain inflammation and isolate it form healthy tissue. Unfortuantley, CSPs are the main reason why a nervous system does not repair itself by regrowing nerves. It was disocvered that a specific receptor on nerve cells (PTPsignma) recognizes CSPGs wihtin scar tissue and binds to them. Their interaction forms a very strong bond that effectively traps nerves permanetly within the scar. NervGen’s peptide binds preferentially to the PTPsigma receptor and effectvely present inhibition from occuring. The end result is release of trapped axons and presention of  new ones form getting trapped in the scar. That enalbles the nervous system to regrow and repair itself in those previously inhibited area. 

NVG-291 (NerGene): Their core technology targets PT

Fosgonimeton (Athira): is a small molecule that can cross the blood-brain varreir and apepars to protect neuronal cells and extend their lives, thus improving patients’ congition and funciton. The molecule is, basically, a grwoth factor enhancer for nerve cells. It promtoes nuron grwoth and creates new connections. This molecuel was also evaluated in a Phase II trail for Parkinson’s disease dementia and dementia with Lewy bodeis. Taht 28 person Phase II study measrued conitive improvement from baseline, using the Alzhimer’s Diease Assessment Scale for cognitive impairment (ADAS-Cog13). Resutls form 5 patients treated with 40 mg fosgonimeton in a modified intent to treat population showed a 7.2 point improvement by week 26, whcih suggets that fosgonimeton may be valuable therapeutic for patients with neurodegeenrative diseases. 

Orexin-2 Receptor Blockers:

–Seltorexant: is a human orexin-2 receptor blocker intended for treatment of agitation or aggression i Alzheimers which is being studied in a Phase II trail. However, J&J will no longer develop the drug for this indication but will continue to evaluate seltorexant for a treatment for major depressive disorder with insomina symptoms. 

Tetrahydrocannabinol (THC):

–TCH+ Melatonin + insulin:

(Cao (WO 2021/011421) discloses compositions which include THC, melatonin and insulin for treating Alzheimer’s diease. In some embodiments, the THC is organic THC, synthetic THC, Dronabinol, delta9-THC or THC-A. The inventors disclose that the composition is useful in reducing amyloid beta (amyloid beta 40 and/or amyloid beta-42). 

Insulin:

Boosting brain insulin action could be a therapeutic option for people at an increased risk of developing metabolic and cognitive diseases such as AD and T2DM. Insulin action is critically important in the developing nervous system, directing differentiation, proliferation, and neurite growth. (Fisher, ” Insulin action in the brain regulates both central and peripheral functions” Am J. Phsy Endocri. Path., 2021 Jul 1; 321(1): E156–E163)

Models:

Neurons presenting hallmarks of AD:

Sun et al. developed a microRNA-based direct reprogramming approach using fibroblasts from individuals with late-onset Alzheimer’s disease ()LOAD). The authors generated neurons presenting the major hallmarks of the disease, including depositions of the proteins Aβ and tau and dysregulation of age-associated transposable elements. Preventing transposable element dysregulation rescued neurodegeneration and reduced Aβ deposition. Sun et al. “Modeling late-onset Alzheimer’s disease neuropathology via direct neuronal reprogramming” Science, 2024. 

Neurodegenerative Cognitive Diseases, Generally:

Type of neurodegenerative Cognitive Diseases:

Neurodegenerative cognitive diseases include diseases such as Alzheimer’s Disease, Dementia with Lewy Body, Parkinson’s Diseases, and Progressive Supranuclear Palsy. Cognitive neurodegeneration is a serious neurological condition that is very common in the elderly. By estimate, about one third of people who live to be over 80 will be diagnosed with some form of neurodegenerative cogntivie disorder. US 2022/0241254 (QAAM Pharmaceutials)

–Acute delirium: is a severe type of cogntive impairment that often afflicts the elderly. The primary indicators are a pronounced change in mental status that rapidly fluctuates, the inability to maintain normal degress of attention, disorganized thinking and vacillating levels of consciousness. Acute delirium can often result from a severe medical illness, recent surgery and the use of several medications or interactions between various medication. The impact of acute delirium on patietns is severe and often chronic, frequently leading to death. While the neurological mechanism by which acute delirium occurs is not completely understood, like with other neurodegenerative cognitive disorders, the neurotransmitter acetylcholine is thought to play a significant role. Undersirable side effects which are discussed below, however, outside the CNS often result. In order to minimize these problems, the adminsitration of drugs that block the peripheral system effects of cholinesterase inhibiotrs is desirable. Unfortuantely, anti-cholinergic frequencly contribue to the underlying problem by causing cenral nervous system toxicity (see below). US 2022/0241254 (QAAM Pharmaceutials)

Causes:

–Decline/Reduction Acetylcholine:

It has been clinically determined that the decline of the neurotransmitter chemical acetylcholine in the brain is one of the primary mechanisms of declining mental function. US 2022/0241254 (QAAM Pharmaceutials)

Treatments:

–Acetyl-cholineseterase inhibitors:

Medications that can prevent or at least minimize breakdown of acetylcholine in the brain provide significant improvement in the cognitive abilites of patients diagnosed with neurodegenerative cognitive disorders. These medications are commonly referred to as acetyl-chlinesterase inhibitors. However, as with any medication, there are side effects with adminsteration of acetylchlinesterase inhibitors such as exacerbation of urinary and fecal incontinence. Other side effects include reduced ehart rate, sweating, vasodilation and increased bronchial secretions. US 2022/0241254 (QAAM Pharmaceutials)

–Quaternary ammonium antimuscarinic drugs (QAAM) (“Antimuscarinic anti-cholinergic drugs (“anti-muscarinics”)):

The quaternary ammonium antimuscarinic drugs (QAAM) are particularly useful because of their ability to antagonize endogenous acetylcholine during periods of excessive acetylcholine production. These ocmpounds share the property that they do not appreciably penetrate the CNS and glycopyrrolate and trospium chloride have been particularly useful in treating pateints in need of periopheral anticholinergic effect on antimuscarinic receptors. The same biochemical property that is advantageous in preventing CNS distribution also limits interstinal absorption, requireing the certin formulations to be taken in the absence of food. US Patent Application 15,736,662, (published as US 10,519,109, QAAM pharmaceuticals)

Attempts to ameliorate the undesirable side effects of acetyl-cholineseterase inhibitors (see above) include adminsitration of antimuscarinic anticholinergic drugs (“anti-muscarinics). These drugs block the peripheral stimulation of acetyl-choline receptors. However, the use of these medications often contribute to cognitive neurodegeneration, which is what the acetyl-cholinesterase inhibitor is inteded to treat in the first place. US 2022/0241254 (QAAM Pharmaceutials)

—-Types of QAAMs:

Currently available quaternary ammonium anti-cholinergic muscarinic receptor antagonists compositions occur as a salt, with the quaternary ammonium cation and a non-organic anion. US Patent Application 15,736,662, (published as US 10,519,109, QAAM pharmaceuticals)

——Glycopyrrolate (aka glycopyrronium bromide): is a bromide salt with a quaternary ammonium counterion with teh chemical name of 3-[cyclopentyl (hydroxy)pheny-lacetoxy]-1,1-dimethyl pyrrolidnium bromide, a molecular formula of C19H28BrNO3 and a MW of 398.34. US Patent Application 15,736,662, (published as US 10,519,109, QAAM pharmaceuticals)

——Trospium chloride: is a quaternary ammonium salt with the chemical name of 3 (2 hydroxy-2,2 dippehnylacetoxy) spiro[bicyclo[3.2.1]octain-8,1’pyrrolidin]1/-ium chlrodie, the molecualr formula is C25H30CINO3 and its MW is 427.97. US Patent Application 15,736,662, (published as US 10,519,109, QAAM pharmaceuticals)

—-Formulations and Production of QAAMs:

US Patent Application 15,736,662, (published as US 10,519,109, QAAM pharmaceuticals) discloses glycopyrronium fatty acid salts produced by counterion exchange reactions between glycopyronium bromide and fatty acid salts of alkali and alkaline earth metals wherein an excess of a free fatty acid (“free fatty acid” is fatty acid in its free form, which is different from the fatty aid in its ionized form (salt form) in the reaction mixture stabilizes the glycopyrronium fatty acid salt and reduces the formation of impurity, Acid A. Favorable partitioning of the glycopyrronium moiety into the organic pphase (alone with the fatty acids) and partitioning of the bromide into the aqueous phase preferably uses water and methyl tetrahydrofuan. While the glycopyrrnium fatty acid salts are unstable with respect to hydrolysis under the reaction conditions and are isolated as oily products an excess of the fatty acid in the reaction mixture stabilizes the glycopyrronium fatty acid salt and reduces the formation of the hydrolysis byproduct impurity, Acid A. Methods of manufacturing glycopyrronium fatty acid salts preferaly include use of a molar excess of the fatty acid. In some embodimetns, at least 0.2 molar equivalent of excess free fatty acid is added to the reaction mixture to form a glycopyrronium fatty acid salt. Since excess free fatty acids stabilize the formulations, this may result in enhanced bioavailability of the glycopyrronium moiety. The QAAM is produced with a lipophilic anion as the anionic component of a salt. Preferred salts come from a family of medium and long chain fatty acids (stearic acid, lauric acid, linolenic acid, capric acid and myristic acid. The salt of the QAAM (cation) and the fatty acid (anion) can be produced through organic chemistry reactions referred to as “ion swapping” or “counterion exchange”. In such a reaction, the QAAM compound as the current elemental salt (glycopyrrolate hydrobromide, tropsium chloride) is placed in a biphasic solution with the elemental salt of an omega-3 fatty acid such as alpha-linolenic acid. The solution is subjected to variations in temperature, pH and agitation to produce a salt that is selectively extracted into the organic phase. The synthesized fatty acids/QAAM salt (e.g., glycopyrronium caprate, glycopyrronium palmitate, glycopyrronium Linoleate) are useful as an individual product for the treatment of various diseases involving excessive acetylcholine activity in human. Adding at least 0.2 molar equivalents of excess free fatty acids into a preparation with fatty acid salts and glycopyrronium bromide in a water/Me-THF system stabilized the reaction mixture and allowed for the formulation of glycopyrronium fatty acid salts. The excess free fatty acid is relative to the glycopyrronium bromide and fatty acid salt used. For example, for a lauric acid reaction with potassium it is the excess free lauric acid realtive to the glycopyrronium bromide and potassium laurate used. The alrger excesses of free fatty acid (0.6-1.2 molar excess) improved the phase separations, improved stability of the organic extract solutions, and improved stability of the isoalted products.

–Quaternary ammonium antimuscarinic (QAAM) + cholinesterase inhibitor:

The desired goal of treatment is to adminsiter the most efficacious type and quantity of medication to treat the neurological condition without increasing the unwanted side effects of high doses of those medications Appropriate treatment includes quaternary ammonium anti-cholinergic muscarinic receptor antagonists which when aminstered at adequate levels in combination with cholinesterase inhibitors at doses that minimize the adverse effects inherent to uunmitigated high doses of cholinesterase inhbitors. US 2022/0241254 (QAAM Pharmaceutials)

US 2022/0241254, (also published as PCT/US2022/012963 (WO2022164694) ad EP4284337) (QAAM Pharmaceutials) discloses a method for improving cognitive function in a human suffering from a neurodegenerative cognitive disorder which includes adminstering a total daily dose of a cholinesterase inhibitor and a quaternary ammonium antimuscarinic compound wherein the quaternary ammonium antimuscarinic compound is adminsitered in a first drug delivery element configured for rapid absorption into the body and wherein the cholinesterase inhibitor is administered in a second drug delivery element configured for a slower or delayed absorption into the body. In anotehr embodiment, the method includes a first drug delivery element releasing a therapeutic amount of 2-8 mg of quaternary ammonium antimuscarinic compound at a first initial time and at a first rate and a second drug delivery element releasing a therapeutic amount of 3-48 mg of a cholinesterase inhibitor at a second initial time and at a second rate, wehrein the frist initial time is the same as the second initial time and the first rate is different that the second rate. In another embodiment, the first dissolve rate is faster than the second dissolve rate. In an embodimetn, the quaternary ammonium anti-cholinergic muscarinic receptor antagonist is glycopyrrolate or trospium and the acetyl-cholinesterase inhibitor administered to ameliorate the disease is rivastigmine. The quaternary ammonium anti-cholinergic muscarinic receptor antagonist prevents or ameliorates the undersirable side effects of acetyl-cholinesterase inhibitors, which permits the adminsitration of higher doses of acetyl-cholinesterase inhibitors than patients could otherwise tolerate. Preferred auternary ammonium anti-cholinergic muscarinic receptor antagonists are those having very low lipid solubility. As a resutl of theri lwo lipophilicity (the ability of a compound to dissolve in a lipid medium), these molecuels tend not to cross the blood/brain varreir as readily as those having higher lipid solubility. By not crossing the blood-brain barreir, these compound do not interfere with the normal function of acetylcholine in the central nervous system, nor do they interfere with the beneficial effects of acetyl-cholinergic inhibitors for the treatment of neurodegeenrative cognitive disorders. Further, these low lipid solubility quaternary ammonium anti-cholinergic muscarinic receptor antagonist drugs ameliorate the undersided periopheral effects from the use of acetyl-cholinesterase inhibitors, such as urinary and/or fecal incontinence, nausea, bradychardia, bronchorrhea and bronchospasm. The quaternary ammonium anti-cholinergic muscarinic agetns include trospium and glycopyrrolate. Both glycopyrrolate (aka “glycopyrronium bromide) and trospium have a low log P , which is a standard for measuring comparative solubility of a compound in a lipid compared to water. The quaternary ammonium anticholinergic muscarinic agetns may be adminstiered concurrently with any of the various acetyl-cholinersterase inhibitors used to treat neurodegenerative congitive disorders such as rivstigmine. In pateitns with neurodegenerative cognitive disorders being treated with ACEI-QAAM, higher doses of all the acetylcholinesterase inhibiotors are toelrated at elast four times the usual monotherapy dose. For rivastigmine, the maximum monotherapy dose in the US is currently 12 mg/day orally or 9.5 mg/day transdermally. But in some embodiemtns according to the invetnion, dosages up to 48 mg/day orally are used.

Amyotrophic lateral sclerosis (ALS; also known as Lou Gehrig’s disease): 

Lou Gehrig’s Disease is an adult onset nuerological disorder that involves the loss of motor nuerons in the spinal cord, brainstem and motor cortex. ALS leass to progressive muscle weakness and atrophy through the body, ultimately leading to paralysis and death within 3-5 years of symptom onselt. There is no cure for ALS and the only FDA approved medications, riluzole and edaravone, are minimally effective, increasing survival by only 2-3 months in the case of riluzole. Dominant mutations in the Cu-Zn superoxide dismutates 1 (SOD1) gene accounts for aobut 20% of familial forms of the disease and 2% of all cases. The SOD1 gene encodes a metalloenzyme that converts superoxide anions into oxygen and hydrogen peroxide and is thus cirical to cellular antioxidat defense. Promising future treatments include the clustered regularly interspaced short palindromic repeasts (CRISPR)-CRISPR-associated (Cas9) geneome editing system by the introduction of frameshift induced mutations that can disable mutant gene function. Gaj, “in vivo geneome editing improves motor funciton and extends survival in a mouse model of ALS” Sci. Adv. 2017).

ALS is a nuerodegenerative diase that results in progressive paralysis due to the loss of neurons in the CNS. Pateints often have prexisting autoimmne diase. Frontotemporal dementia (FTD) is a group of diorders that occur when nerve cells in the frontal and temporal lobes of the brain are lost. This causes the lobes to shrink, and afffects behavior, personality, language, and movement as well as brain inflammation that worses as muslce function declines.

Etiology:

–Research suggest that C9orf72 mutation accounts for about one third of cases of familial FTD and ALS. It is also positive in a percentage (4-21%) of pateints with apparently sporadic disease. The mutation involves pathologic expansion of a noncoding GGGGCC hezanucleotide repeat of the C9orf72gene.

–About 97% of ALS patients have a misfoled transactive response DNA binding protein called TDP-43, wich disrupts the cells. (Alzheimer’s Treatment, Leverages Natural Repair Mechanism” Genetic Engineering & Biotechnology News, August 2024).

–IL-17A: is a potent inflammatory molecule for which overproduction may cause many cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). IL-17A blockage may slow down the progression of ALS disease. Treatment that lbock IL-17A have already been FDA approved to treat autommune diseases, including psoriasis and rheumatoid arthritis.

Biomarkers:

–TDP43 or SOD are biomarkers for ALS

Treatment:

ATH-1105 (athira): Ahtira showed that ATH-1105 protects spinal motor neurons form ALS relevant insults. (Front, Neurosci, 2024: 18: 1348157).

Huntington’s Disease (HD):

Hutington’s Disease is an incurable degenerative disease caused by a single gene defect that is passed down through families. The genetic defect is in a gene responsible for production of an inhibitor of brain cell metabolism. The frequency is 1/24,000 births.

Symptoms: The first symptoms, which typically appear in middel age, include mood swings, anger and depression. Later patients develop uncontrolled jerky movements, dementia and ultimately paralysis. Some people die within a decade of diagnosis. The mutant gene contains instructions for the toxic protein, called huntington.

Diagnosis:

–-Biomarkers:

—-Huntington protein (htt) for Huntington disease (HD) is a biomarker for HD. 

Etiology:

–Indels (small insertions or deletion): Trinucleotide repeat (TNR) or triplet repeat:

The gain or loss of 1-50 bp is called an indel. Since condons consist of three bases, insertions or deletions that do not occur in multiples of three will shift the reading frame in the mRA. Such a frameshift mutation randomizes the downstream sequence of amino acids. Frameshift mutaitons often lead to premature termination as 3 in 64 codons are stop codons, or roughly a stop eveyr 20 amino acids in a random sequence.

A special case of insertions is in Huntingtons Disease constains a seuqnece of ghree bases that are repeated, called a trinucleotide repeat (TNR). This repeat sequence is expanded in the disease allele relative to the normal allele. In the case of Huntington dsiease, the repeat unit is in the coding region of the gene, and the triplet encodes glutamine, and expansion results in a polyglutamine region in the protein. A number of other neurodegenerative disorders are due to this kind of mutation.

Treatment:

Recently a drug called Ionis-HTTRx has shown significant effects at suppressing the effectis of the Huntington’s mutation. The drug is a synthetic single strand of DNA customised to latch onto the messenger molecule. The drug works by interception the mRRA and silencing it. The drug is developed by the California biotech Ionis Pharmaceuticals.

Meningitis

Meningitis is an inflammation of the meninges. The meninges consists of three membranes which encase the soft tissue of the brain and spinal cord. The layers of these membranes, from outermost to innermost are the dura mater, the arachnoid mater and the pia mater. Between the aracnoid mater and pia mater is the subarachnoid space (i.e., the space under the arachnoid matter). The subarachnoid space is filled with a clear serumlike fluid called crebrospinal fluid (CSF). The CSF provides nutrition to the CNS, while also providing a liquid cusihion for teh sensitive brain and spinal cord.

Signs and Symptoms: include severe headache, paintul or stiff neck, fever, nausea and comiting. Early symptoms may be mistaken for flu symptoms. Phtophobia may also be noted.

Causes: Many different microrganisms can cause an infection of the meninges. Some of the more common are discussed here. Also see bacteri, viruses, parasites and fungus for further discussion of some of the microorganisms.

Meningitidis caused by bacteria

1. Neisseria meningitidis: appears as gram-negative diplococci and is commonly known as the meningococcus. The organisms casues the most serious form of acute meningitis and accounts for 15-20% of all meningitis cases. Most cases occur in young children, becasue vaccination of otherwsie healthy children against this disease is not recommended until age 11. Because meningococci do not survive long in the environment, these bacteria are usually acquired through close contact with secretions or droplets. Meningococcal meningitis has a sporadic or epidemic incidence in late winter or early spring. The continuing reservoir of infection is humans who harbor the pathogen in the nasopharynx. The scene is set for transmission when carriers live in close quarters with nonimmune individuals, as might be expected in families, day care facilities, college dormitories and military barracks.Although 12 different strains with different capsular antigens exist, serotypes B, C and Y are responsible for most infectdion in the U.S. The bacterium enters the body via the upper respiratory tract, moves into the blood, rapidly penetrates the meninges and produces symptoms of meningitis.

The different sialic acid (serogroups B, C, Y, and W-135) and nonsialic acid (serogroup A) capsular polysaccharides expressed by Neisseria meningitidis are major virulence factors and are used as epidemiologic markers and vaccine targets. However, the identification of meningococcal isolates with similar genetic markers but expressing different capsular polysaccharides suggests that meningococcal clones can switch the type of capsule they express. See Wenger

2. Streptococcus pneumoniae: also referred to as pneumococcus caseus the majority of bacterial pneumonias. Meningitis is also caused by this bacterium. It is the most frequent cause of community acquired meningitis and is also very severe. About 25% of pneymococcal meningitis patients will also ahve pneumococcal pneumonia. Two vaccines are available for S. pneumoniae, Prevanar which is recommended as part of the childhood immunization schedule and Pneumovax 23, which is available for adults. Crurent recommendations for unvaccinated adults call for initial vaccination with Prevnar, followed by Pneumovax 6-12 monhts later.

3. Haemophilus influenzae: The meningitis caused by this bacterium is severe. Before the vaccine was introduced in 1988, it was a very common cause of severe meningitis and death.

4. Listeria monocytogenes: is a gram positive bacterium that ranges in morphology from coccobacilli to long filaments in palisades formation. Listeriosis in healthy adults is often a mild or subclinical infection with nonspecific symptoms of fever, diarrhea and sore throat. However, listeriosis in elderly or immune compromised patients usually affects the brain and meninges and results in septicemia. The apparent reserovir appears to be soil and water.

Meningitidis caused by fugus

1. Crytococcus neoformans: causes a more chronic form of meningitis with a more gadual onset of symptoms, although AIDS patients may see a fast onset. The primary ecological niche of C. neoformans is the bird population. It is prevelent in urban areas where pigeons congregate and it proliferates in the high nitrogen environment of droppings that accumulate on pigeon roosts. Systemic cryptococcsis requries immediate treatment with amphotericin B and flu conazole over a period of weeks or monthgs. There is no prevention.

2. Coccidioides speces: Thsi fungus causes a condition known as “Valley Fever” in the U.S. Southwest. The morphology of Coccidioides is very distinctive. at 25C it forms a moist white to brown colony with abundant, branching, septate hypahe. These hyphae fragment into thick walled, blocklike arthroconidia. There are two species that casue this disease. C immitis causes disease in California and C. posadasii casues disease in northern Mexico, Central and South American and the American Southwest, especially in Arizona. This is a true systemic fungal infection of high virulences, as opposed to an opportunistic infection. It usually beings with pulmonary infection but can disseminate quickly throughout the body. All persons inhaling the arthrospores probably develop some degree of infection, but certain groups have a enetic susceptibility that gives rise ot the more serious disease. After the arthrospores are inhaled, they develop into spherules in the lungs. These spherules release scores of endospores into the lungs.

Meningitidis caused by Viruses:

1. Zika Virus: Starting in 2015 an epidemic of babies born with abnormally small heads became obvious in Brazil. The cause was determiend to be the Zika virus, an RNA virus in the Flaviviridae family. It is closely related to the viruses cuasing dengue fever, West Nile fever and yellow fever. . When adults are infected with Zika, they can experience a range of symptoms, from none at all, to a skin rash, conjunctivitis and muscle and joint pina. The virus also seems to trigger Guillain-Barre syndrome in some adults which is a neurological condition that can occur after infections with certain bacteria and viruses, and soemtimes after exposure to vaccines. In late 2016, Florida started releasing genetically modified male mosquitoes near Key West. When females mate with these males, their offspring die.

2. Poliomyelitis (Polio): is an acute enteroviral infection of the spinal cord that can cause nuerosmusular paralysis. Because it often affects small children, it was called infantile paralysis. No civilizaiton or culture has escaped the devastation of polio. The poliovirus is in the family Picornaviridae, genus Enterovirus, named for its small size and its RNA genome. Humans are the only known reservoir. The virus is passed within the population through food, water, hands, objects contaiminated with feces and mechnaical vectors. The maintstay of polio prevention is vaccination as early in life as possible, usually in four doses starting at about 2 months of age. Adult candidates for immunization are travelers and members of the armed forces. The two forms of vaccine currently in use are inactivated poliovirus vaccine developed by Jonas Salk in 1954, and oral poliovirus vaccine developed by Albert Sabin in the 1960s. In very rate instances, the attenuated virus reverts to a neurovirulent strain taht causes disease. For this reason, IPV, using killed virus, is the only vaccine used in teh U.S.

3. Arboviruses: Most arthropods that serve as infectious diseases vectors feed ont he blood of hosts. Except during epidemics, detecting arboviral infections can be difficult. The patient’s history of travel to endemic areas or contact with vectors, along with serum analysis is highly supportive. Rapid seriological and nucleic acid amplification tests are availabe for some of the virsues. Arboviruses that cause encephalitis include the West Nile Virus, St. Luis Encephalitic Virus, La Crosse Virus, Powassan Virus, Jamestown Canyon Virs and Easter Equine Enecephalitis Virus.

4. Rabies: is a slow, progressive zoonotic disease characterized by a fatal encephalitis. Infection with rabies virus typically beings wehn an infected animal’s saliva enters a puncture site. Untreated rabies proceeds through several distinct stages that almost inevitably end in death, unless post exposure vaccination is performed before symptoms bengin. Virulence is assocaited with an envelope glycoprotein that seems to give the virus its ability to spead in the CNS and to invade certain tyeps of nueral cells. The primary reservoirs of the virus are ewidl mammals such as canines, skunks, raccoons, baders, cats and bats. Both wild and domestic mammals can spead the disease to humans through bites, scratches and inhalation of droplets. A bite from a wild or stray animal demands assessment of the animal, meticulous care of the wound and specific treatment regimen. Rabies has been transmitted to humans in the absence of a bite, aerosols of bat saliva are thought to be capable of transmitting the virus. For that reason people who have found a bat in their hosue can be encouraged to undergo the postexposure prophylaxis regimen.

Meningitidis caused by Parasites:

1. Naegleria fowleri: can occur in people who have been swimming in warm, natural bodies of freshwater. Infection can begin when amoebas are forced into human nasla passages as a result of swimming. Once the amoeba is inoculated intot he favorable habitat of the nasal mucosa, it burrows in, multiples and uses the olfactory nerve to migrate into the brain. Naegleria advances so rapidly that treatment usually proves futile. Studies have indicated that early therapy with amphotericin B, sulfadiazine or tetracycline in some combinations can be of some benefit. Public swimming pools and baths must be adequately chlorinated and checked periodically for the amoeba.

2. Acanthamoeba: This protozoan differs from Naegleria in its protal of entry. It invades broken skin, the conjunctiva and occasionally the lungs and urogenital epithelia.

3. Toxoplasma gondii: this protozoal infection in the fetus and in immunodeficient people, especially those with AIDS, si severe and often fatal. Although infection in otherwsie healthy people is generally unnoticed, recent data suggest that it may have subtle but profoudn effects on their brain and the responses it controls. People with a history of Toxoplasma infection are often more likely to display thrill seeking behaviors and seem to ahve slower reaction times. Most cases of toxoplasmosis are asymptomatic or marked by mild symptoms such as sore throat, lymph node enlargmenet, and lwo grade fever. T. gondi is a very successful parasite with so little host specificity that it can attack at least 200 species of birds and mammals. The parasite undergoes a sexual phase in the intestine of cats and is then released in feces, where it becomes an infective oocyte that survives in moist soil for several months. These forms eventually enter an asexual cyst state in tissues, called a pseydocyte. Humans appear to be constantly exposed to the pathogen. Many cases are caused by ingesting pseudocytes in undercooked contaminated meat and other sources include contact with other mammals or even dirt and dust contaiminated with oocysts.

Meningitidis caused by Prions:

Prions are proteinaceous infectious paricles containing no genetic material. They are known to cause diseases called transmissible spongiform encephalopathies, neurodegenerative diseases with long incubation periods but rapid progressions once they being. The human TSEs are Creutzfeldt-Jakob disease.

Other Microogranisms which cause Neurological Disease

Tetanus: is a neuromuscualr diasese which is casued by Clostridium tetani, a gram positive spore forming rod. It is a common residue of cultivated soil. C tetani releases a powerful exotoxin that is a neurotoxin, tetanospasmin, that binds to gartet sites on peripheral motor nuerons, spinal cord and brain, and in the sympathetic nervous symtems. The toxin acts by blocking the inhibition of musle contraction. Without inhibition of contraction, the muscles contract uncontrollably, resulting in spastic paralysis. The first symptoms are clenching of the law, followed in succession by extreem arching of the back, flexion of the arms and extension of the legs.

Botulisms: is associated with eating poorly preserved foods and is casued by Clostridium botulinum, an endospore forming anaerobe that does its damage through the relase of an exotoxin, C. botulinum which commonly inhabits soil and water and occasionally the intestinal tract of animals.

Parkinson’s Disease:  (See outline)

Tauopathies:

Tauropathies are diseases caused by misfolding of tau proteins in a pateint’s brain. The resulting prions replicate spontaenosuly in the frontal lobe and form abnormal protein aggregations. Tau prions have been found in patients with frontotemporal dementia (FTD), postraumatic stress disorders (PTSD), demential pulistica and chronic traumatic progressive supranuclear pasly (PSP and chronic traumatic encehalopathy (CTE).

Researches are working with heat shock protein such as Hsp90 as a way to treat neurodegenerative diseases possibly caused by tau.

Rare Genetic Neurological Diseases:

Aromatic L-amino acid decarboxylase Deficiency (AADC): is a rare genetic disorder that affects the production of some neurotransmitters, which are chemical messengers that allow cells in the nervous system to communicate with eath other. Affected individuals may experience symptoms such as delays in gross motor function (head control, sitting, standing, and walking), hypotonia (weak muscle tone) and developmental and cognitive delays.

The FDA approved Kebilidi (eladocagene exuparvovec-tneg), an adeno-assocaited virus vector based gene therapy for the treatment of adult and pediattric patients with AADC deficiency. Kabeilidi is adminsitered via four infusions in one surgical session into a alrge structure in the brain involved in motor control. It should be admisitered in a medical center that specializes in pediatric stereotactic neurosurgery –a technique that uses imaging and special equipment to deliver therapies to specific areas in the brain. After infusion of Kebilidi, treatment results in the epxression of AADC and subsequent increase in the produciton of dopamine, a critical neurotransmitter in the brain assocaited with movement, attention, learning and memory. Kebilid was approved using the accelerated approval pathway.

Spinal Muscualr Atrophy (SMA):

–Pevalence: Symptoms:

SMA is an autosomal recessive neuromuscular disease caused by deletion or mutation of the SMN1 gene. It is characterized by a progressive loss of motor neurons resulting in muscle weakness. The disease affects 1 in 11k live birth before the era of treatment SMA was a leading genetic ause of mortaility in infants. SMA is a devastating autosomal recessive neuromuscular disorder characterized by a progressive loss of spinal motoneurons and elading to muscle weakness and atorophy. Incidence is about 1:11k births and a carreir frequency 1 in 47-72 individuals. In all SMA pateints present with muscle weakness and atrophy predominantly visible in the proximal muscles of the shoulder and pelvic girdle, hpo/areflexia, fasciculations in the denervated muscles (for example fasciculations of tongue muscles are frequently seen in infants with SMA) and skeletal deformities, including soliosis and contractures. Weaness of respiratory muslces may lead to respiratory failure and exposes the affected pateints to the increased risk of infections. SMA patients often require gastrostomy due to feeding problems resulting from impaired swallowing and gastroesophageal dysmotility. (Kotulska, “Recombinant Adeno-Assocaited Virus Serotype 9 Gene therapy in spinal muscular atrophy” Frontiers in Neurology, 2021).

–Treatment:

–—Antisense oligonucleotides:

Intrathecal and oral antisense oligonucleotides which bind to pre-mRNA of SMN2 gene and increase the translation of fully functional SMN protein has been used for treatment. The FDA has approved nusinersen which is an antisense oligonucleotide modulating SMN2 splicing. Binding to a specific sequence in the SMN2 pre-mRNA, it promotes generation of full lenght SMN2 mRNA and functional SMN prtoein. It is adminstiered intrathecally with four loading doses of 12 mg given onn days 1, 14, 28 and 63 followed by a maintenance dose every 4 months. Te phase III, randomized, doulbe-blind and sham controlled ENDEAR study showed that nusinersen improved survival, muscle funciton, and developmental motor milestones in infnts with SMA1. (Kotulska, “Recombinant Adeno-Assocaited Virus Serotype 9 Gene therapy in spinal muscular atrophy” Frontiers in Neurology, 2021

In 2021, risdiplam (RO7034067), which is also an SMN2 mRNA splicing modifier was approved by the FDA and EMA for the treatment of SMA in patients 2 months of age or older, with a clinical diagnosis of type 1-3 SMA or with 1-4 SMN2 copies. Risdiplam is adminsitered orally and is currently used in several clincal studies in patietns with various types of SMA, including presymptomatic. (Kotulska, “Recombinant Adeno-Assocaited Virus Serotype 9 Gene therapy in spinal muscular atrophy” Frontiers in Neurology, 2021

—-Gene replacement therapy.

SMN1 gene replacement is a therpy for SMA. Onasemnogene abeparvovec uses the adeno-associated virus 9 (AAV9) vector to deliver the SMN1 gene. Phase 1 and phase 3 clinical trails showed that a single adminsitraiton of onasemnogene abeparvovec resutled in improvement of motor functions in the majority of infants with SMA. The drug was approved for medical use in the US in 2019 and in Japan and EU in 2020. (Omasemnogene abeparvovec is a gene therapy medicianl product that expresses the human SMN prtoein. In contrast to other therapies, nusinersen and risdiplam, which alter the splicing of SMN2 gene, onasemnogene abeparvovec is designed to deliver a full lenght functional copy of the human SMN1 gene. It is a non-replicating recombinant adeno-associated virus serotype 9 (AAV9) based vector containing the cDNA of the human SMN gene under hte control of the cytomegalovirus enhancer/chicken-beta-actin hydrid promoter. In preclincal study in mice it was hsown that AAV9 virus, in contrast to AAV8 and AAV6, crossed the blood brain barrier and efficiently targeted cells of the CNS. Kotulska, “Recombinant Adeno-Assocaited Virus Serotype 9 Gene therapy in spinal muscular atrophy” Frontiers in Neurology, 2021

How Drugs are administered for Nuerological Diseases

Intrathecal administration: This is a route of adminsitration of drugs into the spinal canal or subarachnoid space so that it reaches the cerebrospinal fluid (CSF). Drugs which need to be administered so as to avoid being blocked by the blood brain barrier such as those drugs which need to be adminsitered to prvent infection, particularly post-neurosurgical, should be adminsitered this way.

Alexion

Hemolytic uremic syndrome (HUS) Generally

HUS is classified as typical versus atypical, and most cases are assocaited with acute kidney injruy. Typical HUS is caused by Shiga toxin producing organisms (most commoly E. coli and Shigella dysenteriae). The mianstay of therapy is supportive care. Atypical HUS (aHUS) is most commonly caused by defects in the regulation of the alternative pathway of complement. (Brodsky, US 2018/0246082). 

HUS most frequently occurs in children under the age of 5, with an annual incidence of 6.1 cases per 100k children. The presentation is generally heralded by diarrhea, which is often bloodly. Most cases (including more than 90% of those in children, are secondary to infection with Escherichia coli serotypes (see below). (Noris, “Ayptical Hemolytic-Uremic syndrome” New England J. Medicine, 2009, 361, 1676-87. )

HUS is characterized by thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure. Thrombocytopenia can be diagnosed as having one or more of (i) a platelet count that is less than 150k mm3 (e.g., less than 60k mm3), (ii) a reduction in platelet survival time, reflecting enhanced platelet disruption in the circulation and (iii) giant platelets observed in a peripheral smear, which is consistent with secondary activaiton of thrombocytopoiesis. Microangiopathic hemolytic anemia can be diagnosed as having one or more of (i hemoglobin concentrations that are less than 10 mg/dL (e.g., less than 6.5 mg/dL), (ii) increased serum lactate dehydrogenase (LDH) concentrations (e.g., greater than 460 U/L), (iii) hyperbilirubienia, reticulocytosis, circulating free hemoglobin and low or undetectable haptoglobin concetnrations and (iv) the detection of fragmented red blood cells (shistocytes) with the typical aspect of burr or helmet cells in the peripheral smear together with a negative Coombs test (Kaplan (1992), ISBN 0824786637, Informa Health Care and Zipfel, Springer (2005), ISBN 3764371668. 

Various Types

HUS is classified into three primary types: (1) HUS due to infections, often associated with diarrhea (D+HUS), with the rare exception of HUS due to a severe disseminated infection caused by Streptococcus; (2) HUS related to complement abnormalities or related to factor-ADAMTS13 deficit, such HUS is also known as “atypical HUS” and is not diarrhea associated (D-HUS); and (3) HUS of unknown etiology that usually occurs in the course of systemic diseases or physiopathologic conditions such as pregnancy, after transplantation or after drug assumption. (Bertoni, World J. Nephrol. 2013 Aug 6; 2(3): 56–76.

Hemolytic uremic syndrome (HUS) is characterized by actue onset of non-immune hemolytic anemia, thrombocytopenia and acute renal failure. Two groups of cases have been defined, typical D+ (or epidemic) and atypical D- (or sporadic). Typical HUS (D+) usually follows a well defined prodromal illness that is often a gastroenteritis and tends to have a good outcome. Atypical D-HUS is characterized by the absence of antecedent diarrhea, insidious onset, tendency to relapste and, in most studies a poor outcome. (Al-Eisa, Pediatr Nephrol (2001) 16: 1093-1098. 

D+HUS (Stx-Associated HUS)

Diarrheal-associated HUS ( D+HUS) is the most common form of HUS, accounting for more than 90% of cases and is caused by a preceding illness with a shiga-like toxin producing bacterium, e.g., E. coli 0157:H7.

D+HUS is the form characterized by a preceding infection with a Shiga toxin secreting pathogen, typically E. coli O157:H7. This pathogen causes painful and typically bloody diarrhea and about 10% of those affected subsequently develop D+ HUS. This subtype is the most common (about 95%) with a reported incidence of 2 cases per 100k persons per year. Renal function recovers in the majority of patients. (Kavanagh, Annul. Rev. Med. 2008: 59: 293-309)

In children, the disease is most commonly triggered by Shiga-like toxin (Stx) producing E. coli and manifests with diarrhea (D*HUS), often boody. Cases of Stx-E. coli HUS, aobut 25%, which, hoever do not present with diarrhea, have also been reported. Acute renal failure manifests in 55-70% of cases, however, renal funciton recovers in most of them. (Noris “Hemolytic uremic syndrome” Am Soc Nephrol 16: 1035-1050, 2005)

Transmission:

Stx-producing E. coli colonize in healthy cattle intestine but also have been isolated from deer, sheep, goats, horses, dogs, birds and flies. They are found in manure and water troughs in farms, which epxlains the increased risk for infection in people who live in rural areas. Humans become infected form contaminted milk, meat and water (water born outbreaks have occured as a result of drinking and swimming in unchlorinated water). (Noris “Hemolytic uremic syndrome” Am Soc Nephrol 16: 1035-1050, 2005)

Diagnosis/Symptoms:

The disease is characterized by prodromal diarrhea followed by acute renal failure. The average interval between E. coli expousre and illness is 3 days. Illness typically begins with abdorminal cramps, and nonbloody diarrhea. Diarrhea may become hemorrhagic in 70% of cases usually within 1-2 d. Vomiting occurs in 30-60% of cases, and fever coccurs in 30%. Leukocyte count is usually elevated. Stx-HUS is not a benign disease. 70% of patietns who develop HUS require red blood cell transfusion, 50% need dialysis and 25% have neurologic involvement, including storke, seizure and coma. After infection Stx-E. coli may be shed in the stools for several weeks after the symptoms are resolved, paritculalry in children. Diagnosis rests on detect of Stx-E. coli in stool cultures. (Noris “HemolytiTrc uremic syndrome” Am Soc Nephrol 16: 1035-1050, 2005)

Treatment:

There is no treatmetn of proven value, and care during the acute phase of the illness is still merely supportive. There is no clear consensus on wehter antiotics should be adminsitered to treat Stx-E. coli infection. (Noris “Hemolytic uremic syndrome” Am Soc Nephrol 16: 1035-1050, 2005)

(non-Siga toxin-associated HUS (non-Stx-HUS))

Non-Shiga toxin-associated HUS (non-Stx-HUS) includes a heterogenous gorup of patients in whom an infection by Stx-producing bacteria could be excluded as cause of the disease. It can be sporadic or familial (i.e., more than one member of a family affected by the disease and exposure to Stx-E. coli excluded). Collectively, non-Stx-HUS forms have a poor outcome. Up to 50% of cases progress to ESRD or have irreversible brain damage, and 25% may die during the acute phase of the disease. Genetic studies have documented that the familial form is associated with genetic abnormalities of the complement regulatory proteins. (Noris “Hemolytic uremic syndrome” Am Soc Nephrol 16: 1035-1050, 2005).

Causes:

A wide vareity of triggers for sporadic non-Stx-HUS have been dientified, including various nonepteric infections, viruses, drugs, amlignancies, transplantation, rpegnancy and other underlying medical conditions scuh as lupus. Infections caused by Streptococcus pneumoniae accounts for 40% of non-Stx-HUS and 4.7% of all causes of HUS in children in the US. Neuroamimidase produced by S. pneumoniae, by removing sialic acids form the cell membranes, exposes Thomsen-Friedenreich antigen to preformed ciruclaitng IgM antibodies, which bind to this neoantigen on platelet and endothelial cells and cause platelet aggregateion and endothelial damage. Categories of drugs that have been most frequently reported to induce non-Stx-HUS include anticancer molecules (mitomycin, cisplatin, beomycin and gemcitabine), immunotherapeutic (cyclosporine, tacrolimus, OKT2, IFN and quinidine) and antiplatelet (ticlopidiene and clopidogrel) agents. Teh resik for developing HUS after mitomycin is 2-10%. (Noris “Hemolytic uremic syndrome” Am Soc Nephrol 16: 1035-1050, 2005)

Treatment:

The discovery of mutations in three different coplement regulatory genes provides enough evidence of the involvement of complement activaiton in the pathogenesis of non-Stx-HUS and indicates that complement inhibition could represent a therapeutic target in these patients. Pexelizumab and eculizumab, two humanized mAbs directed agaisnt C5 have been developed and adminsiteration of eculizumab to patietns with paroxymsal noctururnal hemooglobinuria, a disease characterized by a genetic deficiency of surface rpoteins that protect hematopoietic cells against the attack by the complement system, reduced intravascular hemolysis, hemoglobinuria and the need for transfusions. (Noris “Hemolytic uremic syndrome” Am Soc Nephrol 16: 1035-1050, 2005)

Atypical hemolytic uremic syndrome (aHUS) : 

aHUS is a genetic, life-threatening, chronic disease of complement mediated thrombotic microangiopathy, often characterized by microangiopathic haemolytic anaemia with high lactate dehydrogenase (LDH) levels and reduced or undetectable haptoglobin levels, throbocytopenia and acute renal fialure. It affects both paediatric patientsa and adults. Although rare, aHUS has a poor prognosis and is associated with high morbidity and mortality. In one study, progression to end stage renal disease was seen in 56% of adults with aHUS within the first year. (Keating, Drugs, 73: 2013, pp. 2053-2066). 

Hereditable forms of aHUS can be associated with mutations in a number of human complement components including complement factor H (CFH), membrane cofactor protein (MCP), complement factor I, C4b-binding protein, complement fact B and complement ocmponent 3. 

Although onset of aHUS may occur at any age, 40% of patients develop aHUS by 18 years of age. (Greenbaum, “Eculizumab is a safe and effective treatment in pediatric patients with atypical hemolytic uremic syndrome” Kidney International 2016, 89, 701-711). 

Signs & Symptoms:  Symptoms of aHUS include fatigue and microagniopathic anemia. The pathologic hallmark of HUS is the thrombotic microangiopathy (TMA) that can be seen on renal biopsy. The clincial signs of aHUS overlap with those of TTP which is primarily an autoimmune disorder. 

aHUS is a very rare life-threatning disease. It is characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia, and renal filaure. It is differentiated from hemolytic uremic syndrome (HUS) by the absence of diarrhea and Singa toxin-induced infection. (Turk J. Ophthalmol 47; 6: 2017)

Diagnosis and Treatment Monitoring:

A subject can be identified as having aHUS by evaluating blood concentrations of C3 and C4 as a measure of complement activaiton or dysregulation. In addition, a subject can be identified as haivng a genetic aHUS by identifying the subject as harboring one or more mutations in a gene assocaited with aHUS such as CFI, CFB, CFH or MCP. 

–Changes in Biomarker levels:

A change in the concentraiton or activity level of certain biomarker proteins such as TNFR1, C5b-9 and C5a have been shown to be assocaited with aHUS. (mcKnight US 2016/0154009). 

aHUS assocaited biomarker proteins also include proteolytic fragments of complement component factor B (e.g Ba or Bb), coluble C5b9, thrombomodulin, VCAM-1 von Willebrand Factor (vWF), soluble CD40 ligan, prothrombin fragment F1_2, D-dimer, CXCL10, MCP-1, TNFR1, IFNgamma, ICAM-1, IL-1 beta, IL-12p70. aHUS assocaited biomarkers can be assessessed for monitoring and evaluating the status of aHUS in a patient. (WO 2015021166). 

–Particular Assays:

Brodsky, (US 2018/0246082) discloses an assay to distingguish aHUS from other microangiopathic hemolytic anemias. The mtehtod includes incubating serum obtained form a patient suspected of aHUS with a plurality of GPI-AP deficient cells and performing a cell viability assay on the cells. IN an embodiment, the mtethod also includes the step of diagnosing based on a statistically significant increased difference of non-viable cells from the pateint serum as compared to a control. 

 Causes/Mechanisms of Action: aHUS  is usually caused by uncontrolled activation of the complement system. A missing or significantly reduced function of Factor H, either due to missing or reduced protein levels or gene mutation(s) has been demonstrated as important in this disease. Since the glomerular membrane lacks endogenous regulators, continuous cleaveg of C3 occurs at this site, resulting in deposition of complement activation products. 

Among about 200 children with the disease, 50% had mutations of the complement regulatory proteins factor H, MCP or facto I. (Pediatr Nephrol (2008) 23: 1957-1972 

Treatment:

Renal transplantation is the treatment of choice. A problem, however, is recurrence of HUS in the allograft. (Taheri, Archives of Iranian Medicine, 9(2), 2006, 170-172. 

Treatment options for patients with aHUS are limited and generally involve plasma infusion or plasma exchange. Other treatments include.e.g, use of anti-latelet agents, prostacyclin, heparin, fibrinolytic agents and/or steroid. (Ruggeenenti, Kidney Int. 60, 2001 pp. 831-46). In some cases, aHUS patietns undergo uni-or biolateral nephrectomy or renal transplation (Artz, Transplantation, 76, 2003; pp. 821-826. However, recurrence of the disease in treated patients is common. 

(i) Anti-Complement Treatment:

–Administration of Complement Regulators:

          ––Factor H: Chtourou (US2008/0318841) teaches using factor H for producing a drug for treating Uremic Haemolytic Syndrome (UHS).

–Administration of Antibodies against Complement Componen:

          —Antibodies to C5 (eculizumab, Ravulizumab, etc):

A humanized anti-C5 antibody, eculizumab has been reported as promising in patients with aHUS (Noris, “Ayptical Hemolytic-Uremic syndrome” New England J. Medicine, 2009, 361, 1676-87. ). 

The FDA approved eculizumab for aHUS in September of 2011. 

Andrien (US 2017/0298123) discloses that BNJ441 (“Ravulizumab”) relative to exulizumab contains four amino acid substitutions in the H chain, Tyr-27-His, Ser-57-His, Met-429-Leu and Asn-435 Ser (note that positions 429 and 435 of BNJ441 correspond to positions 428 and 434 uner the EU nubmewing system). These mutations were engineered to enable an extended dosing interval verus exulizumab by increasing the circulating half-life by reducing antibody clearnce and increasing the eficiency o f the FcRn-medaited antiboy recylcing. Adrian teaches taht the antibodies are useful for treating a variety of complement associated disorders such as aHUS, PNH and myasthenia gravis. 

Chatelet (American J. Transplantation, 2009, 9, 2644-2645) discloses that chronic blockage of complement C5 with eculizumab in a patient with aHUS previously dependent on frequent plasmapheresis is safe, and leads to maintained rental function, reduced need for blood transfusions and control of TMA and hemolysis in the absence of plasmapheresis.

Chatelet (Am J Transplant, “Safety and long-term efficacy of eculizumab in a renal transplant patient with recurrent atypical hemolytic-uremic syndrom” Am J Transplant 2009 (Nov; 9(11): 2644-5; Epub 2009, Sep 22) discloses efficacy of eculizumab in a patient who presented a recurrence of atypical hemolytic syndrome 3 eyars after renal transplantation. Based upon the dose regimen determeind for PNH, the patient received 4 doses of eculizumab, 900 mg IV every 7 days, followed by a maintenance dose of 1200 mg every 14 days. After 7 months of treatment and without concomitant plasmapheresis, schistocytes decreased to 0.5%, haptoglobin increased to within normal limits, creatinine levels stabilized and no further episodes of diarrhea were reported.

Mache (“complement inhibitor Eculizumab in atypical hemolytic uremic syndrome” Clin J Am Soc Nephrol 4: 1312-1316, 2009) discloses that a single dose of eculizumab (60 mg, using a 40 min intravenous infusion) resulted in normalization of platelet counts within 3 days and haptoglobin levels within 5 days in a 17.8 year old boy with HUS. ubsequently, renal function improved again and about 2 weeks after recovery of complement hemolytic activity, aHUS replapsed and PCr increased. Repetive doses of eculizumab again led to a normalization of haptoglobin levels within 6 days. Only minor renal recovery (PCr 9.2 mg/dL) ensured and severe hypervolemic hypertension required ehmodialysis again.

Rother (US Patent Application, published as US 2020/007191) discloses a method of treating myasthenia gravis (MG) in an anti-AChR antibody positive patient which includes admionstiering eculizumab at 600 mg once per week for the first four weeks followed by a minatenance dose of at least 900 mg of eculizumab every two weeks

——Dose Based on age/sex/weight:

Greenbaum, (“Eculizumab is a safe and effective treatment in pediatric patients with atypical hemolytic uremic syndrome” Kidney International 2016, 89, 701-711) discloses a clinical trail in paitents with aHUS aged less than 18 years. Greenbaum teahes a schedule of eculizumab does administraiton based on the patient weight. For example, for a patient over 40 kg, 900 mg weekly x 4 and a 1200 mg maintenance dose at week 5 and then 1200 mg q2 week. Overall, the approved pediatric dosing resulted in eculizmab concentraiotn of 50 to 700 ug/ml for all age cohorts. 

Gruppo (N Engl J Med 360: 5 (January 29, 2009) discloses hematologic and renal improvement within 48 hours after initiation of eculizumab and a remission occurred within 10 days. An eculizumab dosing regimen of 600 mg every 2 weeks continued for 4 months, to date, with sustained clinical remission.

McNight (WO 2015/021166) discloses treating aHUS with a suitalbe dose of an anti-C5 antibody that can depend on a variety of factors such as the age, sex and weight of a subject to be treated. McNight discloses various administration schedules depending on the body weight of the subject such as a body weight less than 40 but greater than or equal to 30 kg, or less than 30 but greater than or equal to 20 kg or less than 20 but greater than or equal to 10 kg. For example, in the case of a subject who is less than 20 but greater than or equal to 10 kg, the antiobdy is adminsitered for at least 4 weeks under the folloiwng schedule: at least 500 mg once a week for one week; at least 200 mg of the antibody oncde durin gthe second week; at at least 200 mg of the anitbody bi-weekly therfater. 

NCT02949128 (Alexion, published 10/27/2016) discloses a single arm study of ALXN1210 in treatment of adolescent patients with aHUS. A single loading odse on Day 1 followed by regular maintenance dosing beinging on Day 15 was based on weight; 40 to less than 60 kg: 2400 mg, then 3000 mg every 8 weeks; 60 to less than 100 kg: 2700 mg loading, then 3300 mg every 8 weeks and greater than 100 kg: 3000 mg loading then 3600 mg every 8 weeks. 

Payton (US Patent Applicaiton No: 16/757,512, published as US 20200254092) discloses a method for treating PNH or aHUS that includes adminstiering an anti-C5 antibody at 2400-3000 mg for a patient weighing 40-60kg, 2700-3300 mg for a patient weighting greater than 60 and less than 100 kg or 3000-36000 mg for a patient weighing more than 100 kg. Exemplary antibodies that can be administered include eculizumab (also known as Soliris), ravulizumab (also known as Ultomiris, ALXN1210 and BNJ441), 7086 antibody (described in US Patent Nos: 8,241,628 and 8,883,158), 305LO5 antibody (described in US 2016/0176954), the SKY59 antibody (described in Fukuzawa T., et al. Rep. 2017, Apr 24; 7(1): 1080) and REGN3918 antibody (alsko known as H4H12166PP and described in US 20170355757). The anti-C5 antibodies can also include substitutions that enhance the binding affinity of the antibody Fc constant region for FcRn such as the M252Y/S254T/T256E triple substitution (described by Dall’Acqua et al., 2006 J Biol Chem 281: 23514-23524), the M428L or T250Q/M428L substituions (described in Hinton (2004) J Biol Chem 279: 6213-6216 and Hinton (2006) J Immunol 176: 346-356) and the N434A or T307/E380A/N434A substitutions (described in Petkova (2006) Int Immunl 18(12): 1759-69).

Payton (US Patent Application No: 17/057,898, published as US2021/0332147) also discloses methods of treating aHUS in a pediatric patient (i.e., patient less than 18 years) by administrating an anti-C5 antibody such as ravulizumab (also known as ALXN1210 and BNJ441) according to a particular dosage schedule. In one embodiment, 300 mg of the anti-C5 antibody is administered to a pateint weighing greater than 4 but less than 9 kg, 600 mg if the patient weight greater than 9 but less than 20 kg, 900 or 2100 mg for a patient weight more than 19 but less than 30 kg, 1200 or 2700 mg for a patient weighng more than 29 but less than 40 kg and 2400-3000 mg for a patient weighing more than 39 but less than 59 kg. 

           —-Antibodies to C5 and Hemodialysis:  Ayer discloses eculizumab added to hemodialysis and plasmaphoresis therapy for the treatment of aHUS (Turk J. Ophthalmol 47; 6: 2017)

    –Antibodies against MASP2:

The anti-MASP2 monoclonal antibody, OMS721, which blocks the lectin pathway, has progressed to phase 3 in renal indications and has received ophan drug designation for aHUS and IgA nephropathy. In 2017, Omeros opened an open-label multi-centre phase 3 trail. (Ricklin, Molecular Immunogloy 102 (2018) 89-119

–RNAi:

—-RNAi of C5:

One strategy to overcome high target concentration is to target at the RNA or DNA level. Alnylam Pharmaceuticals have developed an RNAi, Cemdistran that is liver targeted (through GalNAc conjugation) and blocks hepatic production of C5. A phase 2 clinical trial of Cemdisiran in aHUS was launched in late 2017. Given that C5 blockage is required extremely rapidly when an individaul presents with acute episode of aHUS and it takes a nubmer of days for C5 to besuppressed with RNAi, it can be speculated that an additional therapeutic agent may need to be used in the initial stages of therapy to rescue renal funciton before C5 levels are subseqeuntly knocked down. (Ricklin, Molecular Immunogloy 102 (2018) 89-119

–-Small Molecule Antagonists:

—-against C5aR1:

While the blckade of C5 prevetns formation of both disease cuasing products, C5a and MAC, the specific interference with any of these effectors individually may provide further insight into disease mechanisms adn provide clinical benefits in some diseases. This is particularly true in the case of aHUS, for which it has not been resolved wither both C5a and MAC act as drivers of the conditions. Avacopan is an orally bioavailable small molecule antagnist of C5aR1, developed by ChemoCentryx (aquired by Amgen) which has progressed to phase 3 trials in AAV. The company obtained orphase disease designation for C3G in 2017. A phase 2 study in aHUS commenced in 2015. (Ricklin, Molecular Immunogloy 102 (2018) 89-119

Immunoglobulin A1 (IgA1) desposition in human tissues and organs is a characteristic of many human diseaes including IgA nephropathy, dermatitis herpetiformis (DH), and Henoch-Schoenlein purpura, and it is responsible for a variety of clinical manifestations such as renal fialure, skin blistering, rash, arthritis, gastroinstestinal bleeding and abdominal pain (HS) (WO 2004/096157).

Specific Types of Diseases

Henoch-Schonlein purpura (HSP): is another IgA1 mediated post infectious vasculities, most often in children ages 2-11, with kidney damage very similar to IgAN (see below).

IgA nephropathy (IgAN, Berger’s disease): is characterized by the deposition of IgA1 in the mesangium of the renal glomerulus and is the most common glomerulonephritis worldwide. In Japan, it constitutes 30% or more of primary renal diseases, and is the most common renal disease. Moreover, 15-30% of the patients with IgA nephropathy achieve renal failure. The IgA depositis arise spontaneously, usually in the second or third decade of life and are thought to be immune complexes. IgA nephropaty is a disease with a poor long term prognosis and it is estimated that about 25% of patients with terminal renal failure who are in need of dialysis treatment have IgA nephropathy as the original disease.

IgA nephropathy is a chronic glomerulonephritis which is characterized in that an IgA immune complex considered to be originated form blood deposits in the glomerulus of the kidney. It has been reported that bout 50% of the patients with IgA nephropathy have a high blood IgA level. It is considered that excessive IgA is produced due to abnormality in the immune system, resulting in IgA immune complex in blood deposits on the glomerulus.

IgA nephrapathy is caused by aberrant glycosylation of IgA molecules, which are subsequently recognized by antiglycan autoantibodeis. Glomerular immune complex deposits can lead to complement activation, which casues podocyte damage either direclty or indirectly with activaiton of mesangial cells and stimulation of cytokines and other downstream immune meditors. (Lambris, “The renaissance of complement therapeutics” (2018))

IgM nephropathy (IgMN): causes nephrotic syndrome and is characterized by IgM mesangial deposits. It is sepculated that these deposits are derived from icrulating IgM aggregates or immune complexes, similar to IgAN.

–Mechanisms of Action

The mechanism of polymeric IgA1 deposition in the kidney mesangium is poorly understood in IgAN. It has been suggested that increased sialic acid content and anionic charge of the pIgA1 molecules may be operational in the IgA1 deposition in human mesangial cells. (Leung, Kindey International, 59, 2001, pp. 277-285) 

–Diagnosis

Diagnosis is typically by renal biopsy, which removed a sample of the kidney tissue for pathological examination. A renal pathologist does immunofluorescent staining of kidney tissues which requires sequential applicaiton of anti-human IgA antibody.

Qui (US  13/439473) discloses a method for diagnosing an IgA or Igm kidney disease by administering to the person a compound which specifically binds IgA or IgM and detecting the compound in the kindey of the mammal. The compound can include a peptide such as the human Fc alphaR1 or streptococcal IgA binding peptide, modified Z domain protein.

Obara (US 8,2426,142 B2) discloses an IgA nephropathy testing method comprising a complex detection step of detecting a complex of human uromodulin and human IgA in a sample derived form urine collected from a subject.

Ishiwata (US 2003/0207828) discloses a novel DNA whose expression level fluctuates in leukocytes of IgA nephropathy patients as well as isoalting the protein encoded by the DNA. Based on this, an antibody recognizing the protein is disclosed and methods for detecting the protein and DNA.

–Treatment

Treatment options for patients that present with abnormal IgA1 deposition include administration of corticosteroids that have immunosuppressive and anti-inflammatory properties, dietary fish oil supplements that reduce renal inflammation, and angiotensin converting enzyme inhibitors that reduce the risk of progressive renal disease and renal fialure (Plaut, WO2004/096157).

To address the problem of IgA1 desposit removal, exogenous proteolytic enzymes have been tested in IgA1 deposition animal models. The proteases, chymopapain and subtilisin act by proteolytic cleavage of IgA1 depositis in the kidney but are not specific for IgA1 and will digest a variety of other proteins (Plaut, WO 2004/096157).

Plaut (US 2005/0136062 A1) disclose the use of bacterial IgA1 proteases to treat IgA1 which specifically cleave IgA1 molecules deposition in tissue and organs. In one embodiment, a pharmaceutical composition for the treatment of IgA1 deposition is provided that comprises an IgA1 protease complexed with an antibody, such as an anti-IgA1 protease antibody.

Links of interest: National Kidney Foundation. Web MD

Companies:  Rockwell Medical

See also: Reperfusion injury under inflammatory diseases

Types of Kidney Diseases 

Examples of kidney diseases include end stage renal disease, acute renal failure, chronic renal failure, polycystic kidney disease, chronic kidney disease, acute tubular necrosis (e.g., renal artery stenosis), infections that reduce kidney function kidney transplantation rejection and urinary tract obstruction. In addition, there are various disorders which are associated with such disorders.

Hemolytic uremic syndrome (HUS):  See outline

Autosomal dominant polycystic kidney disease (ADPKD): is among the most prevalent dominant human disorders. The major manifestation of the disorder is the progressive cystic dilation of renal tubules, leading to renal failure in half of affected individuals by age 50. ADPKD associated renal cysts may enlarge to contain several liters of luid and hte kidneys usually enlarge progressively cuasing pain.

Reeders (US 5,891,628) disclose a novel gene called the PKD1 gene and mutations within this gene which are responsible for about 90% cases of ADPKD. In addition, the gene product and antibodies directed against the product are described as well as methods and compositions for the diagnosis and treatment of ADPKD.

Glomerulonephritis: is a renal disease characterized by bilateral inflammatory cahnges in the glomeruli of the kidneys. Rpadily proressive glomerulonephritis (RPGN) can be caused by any of several underlying conditions, inclding necrotizing and/or crescentic glomerulonephritis with scant or no immune deposits (pauci-immune NCGN), anti-glomular basement mebrane nephritis (anti-GBM nephritis), IgA nephropathy, lupus nephritis and post-streptococcal glomerulone-phritis. In addition, certain diseases other than glomerulonephritis, such as hemolytic uremic syndrome or acute interstitial nephritis, may produce the clinical picture of RPGN. Pauci-immune NGGN can be restricted to the kindey (primary NCGN) or associated with Wegener’s granulmatosis or a systemic disease often classified as microscopic polyarteritis nodosa. (Arnaout US 5,200,319). 

Glomerulonephritis is a disease of the kidney characterized by inflammation and resulting enlargement of the glomeruli that is typically due to immuen complex formation. The accmulation of immune complexes in the glomeruliresults in inflammatory resopsnes, involving inter alia hypercellularity, that can cause total or partial blockage of the glomerulus through, among other factors, narrowing of the capillary lumens. One result of this process is the inhibition of the normal filtration function of the glomerulus. Blockcage may occur in large numbers of glomeruli, directly compromising kidney funciton and often causing the abnormal deposition of proteins inthe walls of the capillaries making up the glomerulus. Such deposition can, in turn, cause damage to glomerular basement mebranes. Those glomeruli that are not blocked develop increased permeability, alloiwng alrge amounts of protein to pass into the urine, a condition referred to as protienuria. (US63555245)

C3 glomerulpathy, C3G, is a rare disease and encompasses a heterogenous gorup fo syndromes encompassing dense deposit disease and C3 glomerulonephritis (C3GN). As with aHUS, C3G is a disease in whihch the complement system is dyregulated, typically within the amplificaiotn look. Unlike in aHUS, the dysregulaion usually affects fluid phase acitvaition. It is clear that systemic acitvaiton of complement leads to high levels of complement deposition in the kindey, particularly as teh glomerular basement membrane. (Ricklin, Molecular Immunogloy 102 (2018) 89-119). 

C3G is primarily driven by excessive complement turnover in the ciruclation due to convertase stabilizing autoantibodies, which mainfests in massive deposition of C3 activaiton fragments in the kidney (mostly on the glomerular basement membrane in the case of dense deposit disease). (Lambris, “The renaissance of complement therapeutics” (2018)). 

Immune complexes in the kidney are notable absent in aHUS and C3G, but are present in other diseases of the kidney. In immune complex glomerulonephritis (IC-MPGN), immune complexes activate the classical pathway and deposits of activated C3 and immunoglobulin are found in the kidney. The disease is heterogenous with varialbe presence or absence of complement gnee mutations, autoantibodies and complement abnormalities in the circulation. (Ricklin, Molecular Immunogloy 102 (2018) 89-119)

Lupus nephritis is a common clinical manifestation and casue of morbility in systemic lupus erythematosus (SLE) in whcih immune complexes deposit in the kidney causing complement activaiton, renal cell damage and thrombotic microangiopathy (TMA). Up to 50% of patiens with SLE will have clinically evident kidney dsiease at presentation during follow-up, renal involvement occurs in up to 75% of patients. (Ricklin, Molecular Immunogloy 102 (2018) 89-119.pertension. (US63555245)

GN is the third leading cause of death in end stage renal disease patients, exceeded only by diabetes and h

–Diagnosis of glomerulonephritis: 

Diagnosis of the condition causing RPGN is essential for teh initiation of appropriate treatment. Renal biopsy has generally been considered to be the msot definite diagnostic procedure in patients exhibiting RPGN. However, the procedure invovles risk and sometimes fails to provide the correct diagnosis because the lesions in the NCGN are often focal and can be missing from a small biopsy specimen. 

Serologic test have diagnostic value in some forms of RPGN. In particular, patients exhibiting RPGN often have circualting auto-antibodies directed against neutrophils and monocytes. the presence of these auto-antibodies, generally referred to as anti-neutrophil cytoplasm antibodies (ANcA) ahs been used as a diagnostic tool ANCA are detected by means of an indirect immunofluorescence assay suing ethanol fixed normal human neutrophils as a substrate. (Arnaout US 5,200,319) discloses a substantially pure protein )p29) which can be isolated from human neutrophils and is capable of binding to auto-antibodies present in the sero of individuals aflficted with Wegener’s granulomatosis. A method of detecting auto-antibodies diagnsotic for Wegener’s granulomatosis is discloses which includes the step fo contacting a biological fluid to be tested to p29. Any immune complexes formed are detected and used as an indication for the presence of auto-antibodies diagnostic for Wegener’s granulomatosis. A separate method is disclosed for detecting auto-antibodies diagnostic for pauci-immune necrotizing and/or crescentic glomerulonephritis which involves contacting a sample with myeloperoxidase and detecting immune complexes formed. 

–-Symptoms of glomerulonephritis: include proteinuria, reduced glomerular filtartion rate, serum electrolyte changes including azotemia (uremia, excessive blood area nitrogen-BUN) and salt retention, leading to water retention reuslting in hypertension and edema, hematuria and abnormal urinary sediments including red cell casts, hypoalbuminermia, hyperlipidemia and lipiduria. (US63555245).

–—Treatment of Glomerulonephritis:

—-anti-C5 anibodies:

(US63555245) disclsoes anti-C5 antibodies taht bind to complement component C5 which can be admisntiered after the appearance of GN smptoms. 

Chronic kidney disease (CKD): affects more than 20 million Americans and is associated with high morbidity and mortality. The progressive deterioration of kidney function in CKD leads to retention of many substances, including phosphorus (P) that are normally excreted by the kidney. ADPKD is inhreited as an autosomal dominant disorder. Three distinct loci have been shown to cause phenotypically indistinct forms of the disease, with greater than 85-90% of the disease incidence being due to mutations which map to the short argm of chromosome 16.

Diabetic nepthropathy (DN): is a progressive kidney disease assocaited with longstanding diabetes mellitus. It causes abnormal fluid filtration and increased urinary albumin excretion, eventually leading to kidney failure. Although several treatment have been proposed in addition to the strict control of blood glucose levels, the prognosis of patients with diabetic nephropahty reamins poor as compared to other causes of renal failure. One of the mechanisms involved in DN is a hypercoagulation state that produces numerous microthrombi in the glomeruli. Ishii showed that administration of annexin-2 significantly reduced microalbuminuria and the development of glomerular lesions in a murine model of type 2 diabetes.

IgA and IgM Mediated Kidney Diseases: See outline

Membranoproliferative glomerulonephritis (MPGN): MPGN mainly affects children and adults (median age at onset of disease about 10 years. 50% of the patients present with nephrotic syndrome, the others with mild proteinuria, 20% with macrohematuria. 30% of the patients develop hypertension with onself of disease. Children with MPGN have an unfavourable late prognosis and develop end stage renal disease (ESRD) after about 8-16 years. chronic nephropathies 

–MPGN type II (MPGN II): MPGN II, also termed “dense deposit disease” is a rare disease which is characterized by complement containg dense deposits within the basement membrane of the glomerular capillary wall and followed by capillary wall thickening, mesangial cell prolfieration and glomerular fibrosis. 

–MPGN & MPGNIII: are two more subtypes of MPGN characterized by mesangial cell proliferation and increase in mesangial matrix compbined with a thickening of the glomerular capillary walls. 

Renal Ischemia: may occur in the setting of hypovolemia, hypotension or renal transplantation. Ischemia reperfusion (I/R) injury in the kidney is a common cause of acute renal fialure (ARF). Hemodialysis is currently the only treatment of ARF that is approved by the FDA.

Student of renal I/R injury have demonstrated that mice deficient in complement are protected from injury. Deposition of C3 occurs primarily at the tubular basement membrane and teh reas of deposition correspond with morphologic injury. Thurman (J. Immunology, 2003, 170: 1517-1523) showed that mice deficient in complement factor B, an essential component of the AP pathway, developed substantially less injury after I/R.

Stable Renal Function:

Stable renal function refers to renal function which may be estimated by Glomerual Filtration Rate calculated by Modification of Diet in Renal Disease 7 (MDRD7) or serum creatinine. Generally, stable renal funciton refers to renal funciton which varies by less than 60% between repeated measurements of estimated by Glomerular Filtraiton Rate and serum creatinine. (Frey, US Patent Applicaiton No: 16/340,453, published as US 2019/0276524). 

Conditions Associated with Renal Failure  See outline

1. Erythropoietin (EPO) deficiency: See outline

2. Hyperphosphatemia: See outline

3. Proteinuria: See outline

4. Hyperparathyroidism (HPT): see outline

5. Vitamin D Deficiency: See outline

6. Complement System Upregulation: See outline

Ischemia/reperfusion (I/R) injury represent an acute inflammatory response following trauma, surgery, stroke, heart attack, or other events in which circulation is transiently blocked. I/R occurs when a blood vessel is occluded naturally or by injury for an extended period of time, and the blood flow is restored after an extended period of ischemia. IR is a generatl syndrome that is responsible for both acute and chronic injury to various tissues including, for example, myocardium, central nervous system, hing limb and intestine. IR can result in necrosis and irreversible cell injury (US 13/120125).

Mechanisms of Action: Although the mechanisms responsible for injury remains unclear, one general model is that injury occurs in two stages. The first stage represents intrinsic cell injury that can be due to various processes including hypoxia-induced increased levels of reactive oxygen species (ROS). A second pathway of injury is based on the induction of acute inflammation possible by neutrophil contact with the hypoxia-induced modified cell surface.

–involvement of complement system:

The complement pathway (including the alternative complement pathway ) is a major mediator of I/R injury (US 13/120125).

—-Self-Neo-peptides: A related hypotesis is that recognition of the modified surface is specific and results in activation of the innate immune system via the lectin complement pathway. In this model, intrinsic up-regulation of ROS leads to the exposure of a “neo” self-determinant on the cell surface and activation of the innate immune system. A single clone was identified that restored IP injury in a mouse model. This led to the identification of “non-muscle myosin heavy chain II (NMHC-II) as the target self-antigen for pathogenic IgM. NMHC-II is expressed in all eukaryotic cells and three forms (A, B, and C) of  NMHC-II have been identified. They are highly conserved among mice and humans but the distribution of the three isoforms varies among tissues. 

Ischemia-reperfusion injury can be initiated by clonally specific natural IgM that activates the classical pathway of complement. These studies have led to the identificaiton of pathogenic IgMs and, in turn, the identificaiton of self-peptides that bind natural IgM. US 7,442,783 describes a conserved region within type II NMHC proteins representing the major epitope for binding of natural IgM following ischmeia in an intestinal model.

Carrol (US13668515) describes antibodies that bind to the N2 self-peptide and inhibit this inflammation.

Puro (US2014/0271628 (US/14/206,368)) describes humanized antibodies that specifically bind N2 peptide

A synthetic pepide referred to as N2 which represents the highly conserved epitope within the myosin heavy chain and to which the IgM clone has specific affinity was shown to reduce I/R injury.

The reasons why a chronic inflammatory intestinal disease arises are unclear. Crohn’s disease, for example, is attributed to immunological factors, genetic factors such as polygenic transmission, nutritinal factors such as for example the frequent consumption of candy, and also infectious factors such as rotaviruses, non-capsulated myco-bacterial and pseudomanads.

Diagnosis: 

The definitive diagnosis of a IDD can frequently succeed only through the chronic course.

Treatment: 

Since a causal therapy is not yet possible, the treatment of IIDs like Crohn’s disease and ulcerative colitis is prinicipally aimed at alleviation of the symptoms. The established therapies for IIDs at present are based on unspecific, inflammation inhibiting substances such as glucocorticoids and aminosalicylates. 

Remicade (Centocor) is an approved antibody for treating Crohn’s diease. 

Specific Diseases:

I. Inflammatory bowel disease (IBD): 

Inflammatory bowel disease (IBD) refers to active ulcerative colitis (UC) and active Crohn’s disease (CD). IBD is characterized by excessive and chronic inflammation at various sites in the gastro-intestinal tract. Ulcertaitve colitis and Crohn’s disease are chronic inflammatory disorders of the bowel that fall under the category of IBD.  

IB is a collective term used to describe three gastrointestinal disorders of unknown etiology. Cronhn’s disease (CD), ulcerative colitis (UC and indeterminate colitis (IC). (Singh, US Patent Application 16/536,777, published as US 2020/0088749); see also US 10422807)

Despite greater than fifty years of clinical experience with Crohn’s disease and ulcerative olitis, the precise eitology of these diseases remains unknown and the mobidity high (Mannick, US 2004/0077020A1).

A. Types of IBDs

1. Colitis ulcerosa (ulcerative colitis): Ulcerative colitis is a chronic inflammation of the large intestine. This IDD is chacaracterized by ulcerations with mucosal islands remaining between them. The disease encroaches on the small intestine only in rare cases. In ulcerative colitis, only the mucosa is affected, while in Crohn’s disease affects all wall layers and fistulas often form. Most CD patients experience characteristic period of remission and flare-ups of the disease, often requiring long term medication and/or hospitalization and surgery. The symptoms differ depending on what part of the intestinal tract is inflamed. Symptoms include chronic diarrhea, abdominal pain, cramping, anorexia, and weight loss. Systemic features include fatigue, tachycardia and pyrexia. Chronic or acute blood loss in the bowel may result in anemia and even shock. The most common complication of CD is the presence of obstructions of the inestine due to swelling and formation of scar tissue. Another complication involves sores or ulcers within the intestinal tract. Pateitns with CD are also at increased risk of cancer of both the small and alrge intestine (US 2009/0081658).

There is no single definitive test for the diagnosis of CD. Physicians will evaluate a combination of information from the history and physcial examination of a patient and from results of endoscopic, radiologic and histologic (blood and tissue) tests.

–Treatment:

Because there is no cure for DC, the goal of medical treatment is to suppress the inflammatory response and alleviate the symptoms. The FDA advises that a physican reported endoscopic and histological assessmetn and a pateint reported assessment of signs and symptoms should be included as ideal efficacy endpoints for treatment sutides. The agency has advised against use of Mayo Score and Ulcerative Colitis Disease Activity Index measurements when seeking approval. (“Ulerative Colitis: Clinical Trial Endpoints Guidance for Industry, Draft Budiance). Non-surgical treatment for active disease involves the use of anti-inflammatory (aminosalicylates and corticosteroids), antimicrobial, and immunomodulatory agents. The biologic therapies are targeted towards specific disease mechanisms and have the potential to provide more effective and safe treatment.

—-Anti-inflammatory cytokines (recombinant IL-10 and IL-11) 

–—Cytokine inhibitors: TNF inhibitors such as AbbVie’s Humira.  infliximab (Remicade®) is a chimeric monoclona antibody against TNFalpha, and the first biologic therapy that was approved for CD. IL-12/23 inhibitors such as J&Js antibody Stelara.

—-antisense therapies (ICAM-1) are also being evaluated.

—-integrin therapy such as Takeda’s Entyvio

–—sphingosine-1-phosphate receptor inhibitors: Zeposia by Bristol Myers contains an active substance, ozanimod, which blocks the action of sphingosine-1-phosphate receptors on lymphocytes (cells of the immune system that can attack the body’s own tissues in diseases such as multiple sclerosis or ulcerative colitis). By attaching to these receptors, ozanimod stops lymphocytes from travelling from the lymph nodes towards the brain, spinal cord or intestine, thus limiting the damage they cause in multiple sclerosis and ulcerative colitis.

A number of complementary therapies have been shown beneficial for UC. Curcumin, the probiotic VSL#3 and ale ver have all been shown to at least induce a response in ctrolled traisl in pateints with mild UC who are already using mesalmine. (Moss, “Residual inflmmation and ulcerative colitis in remission” Gastroenterology and Hepatology, 10(3), 2014). 

2. Crohn’s disease: is an unspecific granulomatous inflammation which can affect all sections of the digestive tract from the esophagus to the anus, but is mainly present in the region of the lower ileum and the colon. In about 40% of all cases the terminal ileum is exclusively affected, rarely the esophagus and stomach. Crohn’s disease is an inflammatory bowel disease (IBD) in which inflammation extends beyond the inner gut lining and penetrates deeper layers of the intestinal wall of any part of the digestive system (esophagus, stomach, small intestine, large intestine, and/or anus). It is a chronic, lifelong disease which can cuase painful, often life altering symptoms including diarrhea, cramping and rectal bleeding. It occurs most frequently in the industrialized world and the typical age of onset falls into 2 distinct ranges, 15-30 and 60-80 years of age. The highest mortality is during the first years of disease, and in cases wehre the disease symptoms are long lasting, an increased risk of colon cancer is observed. Crohn’s disease account for about 2/3 of IBD-related physician visits and hospitalization, and 50-80% of Crohn’s disease patients eventually require surgical treatment. Development of Crohn’s disease is influenced by environmental and host specific factors, together with exogenous biological factors such as constituents of the intestinal flora. It is believed that in genetically predisposed individuals, exogenous factors such as infectious agents combine with specific environmental factors to cause a chronic state of improperly regulated immune system function. In this model, microorganisms trigger an immune response in the intestine, and in susceptible people, this response is not turned off (US 2010/0081129).

B. Treatment Strategies:

Treatment for pateints with IBD includes immunosuppressive and immuno-modulating agents such as azathioprine/-mcercaptopurine, methotrexate, tacrolims, and cyclosporine A (CsA). Infliximab which is a chimeric monoclonal antibody targeting tumor necrosis factor alpha has also shown benefit in inducing remission in active CD (Digestive Diseases and Sciences, 47(6), 2002, pp.1362-1368). 

–alpha4beta7 integrain-neutralizing antibodies:

—-Vedolizumab: is a gut specific, alpha4beta7 integrin neutralizing monoclonal antibodywhich does not affect peripheral blood cell counts and appears to clack systemic effects. Vedloizumab is an anti-inflammatory treatment for the management of therapy refractory patients. (Singh, US Patent Application 16/536,777, published as US 2020/0088749); see also US 10422807)

–IL12p40 nuetralizing antibodies: 

—-Ustekimumab (Stelara)  is a IL-12p40 monoclonal antibody which is used to treat IBD. Ustekinumab is specific for IL-12 and IL-23 via theri common p40 subunit and blocks inflammation through these pathways. (Singh, US Patent Application 16/536,777, published as US 2020/0088749); see also US 10422807),

Ustekimuab is approved to treat Crohn’s disease in the US and EP, and ulcerative colitis in the US and in the EU to people who have not responded to more traditional treatment. It was not found effective to treat multiple sclerosis. It has also been used to treat psoriasis. It is adminsitered with by intravenous infusion or subcutaneous injection. 

–IVIG:

Barstow (US20030099635) discloses treating neurodegenerative diseases by oral administration of immunoglobulin.

Reipert (US2009/0148463) teaches that IVIG have been shown to be effective in the treatmnet of MS. 

Tjellstrom (US2002/0114802) discloses a method of treating inflammatory bowel disease (IBD) by orally adminsitering an effective amount of a pooled human polyclonal immunoglboulin preparation.

website of interest: American College of Rheumatology

Rheumatoid arthritis (RA) is a chronic inflammatory disorder that ultimately leads to the destruction of joint architecture. In rheumatoid arthritis, a person’s own immune system attacks the joints by activating the synovial tissue that lines the body’s movable joints, causing inflammation, swelling, pain and eventually erosion of the bone and cartilage and deformation of the joint. An estimated 1.5 million people are diagnosed with moderate or severe rheumatoid arthritis (RA). RA is one of the most common autoimmune inflammatory disorders, with a prevalence of between 0.5-1% in most adult populations.

Prevalence of RA is estimated to be 0.8 percent worldwide, with women twice as likely to develop the disease as men. Untreated, 20 to 30 percent of persons with RA become permanently work disabled within 2-3 years of diagnosis (Rindfleisch, American Family Physician, 72(6), 2005, 1037-1047).

Causes: Pathological Events

The pathogenic events that lead to the development of RA are not fully understood, although the pivotal role that proinflammatory cytokines (i.e., TNFalpha, IL-1beta, IL-6, etc) play in the induction and maintenance of this disease is well documented. Among the many genetic studies of small cohorts, the only genes consistently associated with RA are the MHC (i.e., human leukocyte antigen (HLA) linked genes, on the short arm of human chromosome 6. It has been estimated that about one third to one half of the total genetic contribution to RA can be attributed to genes within the HLA complex.

Deficiency in Complement Components:

Deficieincy of C1q, Clr, Cls or C4 is closely linked to defvelopment of rheumatoid arthrisis (as well as SLE) thought be be due in part to the inability of complement to clear immune complexes and dysing cells. Small complexes are cleaved from the circulation when they bind to complement receptors on macrophages in the speen and liver. Without complement, the complexes can grow too large to be easily cleared. The resulting aggregates can activate the alternative pathway, allowing C3 to be deposited into the matrix, with re-solubilized complexes that can be dealt with by the clearance through the liver and spleen. Failing this, these large complexes are no longer soluble and form deposits in the tissues and become a site of inflammation. Dying cells if not cleared by non-inflammatory CP activity, may serve as sources of altered self-antigens with the potential for inducing autoantibodies. (US Patent Applicaiton No: 15/895,551, published as US 2019/0247560). 

Diagnosis

No single diagnostic test definitvely confirms RA. However, several tests can provide objective data that increase diagnostic certainty. The ACRSRA recommends that baseline laboratory evluations include a complete blood cell count with differential, rheumatoid factor, and erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP). Baseline evlauation of renal and hepatic function also is recommended because these finding with guide medication choices (Rindfleisch, American Family Physician, 72(6), 2005, 1037-1047.

CD93 (C1qR): Crockard (Immunology Letters, 36 (1993) 195-202) disclsoses that levels of C1q receptor (C1qR) were significantly higher on synovial fluid neutrophils from patietns with rheumatoid arthritis compared to normal control subjects. 

Young (WO/2010/087594 and US 13/146876) also discloses that CD93 soluble fragment  in synovial fluid obtained from rheumatoid arthritis patients was significantly higher than that in synovial fluid obtained from osteo-arthritis patients and that the CD93 molecule or its soluble fragment can be effectively used as a diagnostic marker for RA. 

Symptoms

Clinically, RA is a highly heterogeneous disease varying from very mild to severely disabling with upwards of 1 in 20 patients progressing to severe, erosive disease. Joint damage occurs early in disease with the greatest progression to joint abnormalities taking place during the first 6 years. Within 3 years of disease onset, as many as 70% of patients show some radiographic evidence of joint damage. The most commonly used diagnostic criteria are those adopted by the American College of Rheumatology in 1987. A pateint is classified as ahving RA if she has 4 of the following 7 criteria (i) morning stiffness lasting at least one hour (ii) arthritis of 3 or mroe joint areas (iii) arthritis of hand joints (iv) symmetric arthritis (v) rheumatoid nodules (vi) presence of serum rheumatoid factor (RF) and (vii) radiographic changes in hand or wrist joints.

Treatment Strategies

The American Rheumatism Association (ARA) recommends that patients with suspected RA be referred within 3 months of presentation of confirmation of diagnosis and initiation of treatment with DMARDS (see (1) below). In past decades, pharmacologic treatment of RA was managed using a pyramid approach with symptom alleviating treatment at the start of diagnosis. However, a reverse pyramid approach is now favored in which DMARDs are initiated quickly to slow disease progression as early as possible.

(1) Disease Modiyfing Anti-Rhematic Drugs (DMARDs): Many DMARDs have been used in the treatment of other diseases such as cancer and malaria. Antimalarial DMARDs include chloroquine (Aralen) and hydroxycholoroquine (Plaquenil). Other DMARDS include methotrexate (Rheumatrex) and TNF blockers such a sinfliximab, an IgG1 anti-TNFalpha antibody.

Cyclosporin A (CSA) has also been shown to be effective in treatment of patients with RA, although there are side effects such as renal toxicity, hypertension and gastrointestinal complains. In this respect, Hydroxycloroquine (HCQ) has been suggested as a better replacement (Seo, Ann Rheum Dis 2001, 60: 514-517).

Slow-acting antirheumatic Drugs (SAARDs) are a special class of DMARDs where the effects are slow acting.

(2) Immunosuppresive cytotoxic drugs: This class of drugs is used if treatment with NSAIDs and SAARDs have no effect. Examples include methotrexate.

(3) Complement Inhibition: The role of complement in the pathogenesis of animal models of human RA has clearly been demonstrated. For example, immunofluorescence data in rats with collagen-induced arthritis (CIA) showed that aricular cartilage contained IgG and C3. when rats were depleted of complement with cobra venom factor (CVF), the onset of clinical disease was delayed and the development of disease in thse animals correlated with the return of functional complement activity.  (Goodfellow, Clin Exp. Immunol. 2000, 119, 210-216).

(4) Fusion Proteins: Many of the antibodies below and antibody fusion proteins work by pventing both T and B cell activation.

—CTLA4-Fc: A new drug called Orencia is a fushion of cytotoxic T lymphocyte antigen-4 (CTLA4) and a gradment of the Fc portion of IgG1 which purportedly blocks the costimulatory signal between antigen-presenting cells and T cells, preventing T cell activation has been approved by the FDA for the treatment of rheumatoid arthritis. Phase 3 results showed that half of Orencia patients who fialed traditional anti-TNF therapy acheived at least a 20% improvement in the signs and symptoms of the disease compared with one fifth of patietns receiving placebo. However, only one patient in ten experienced 70% improvement. Thus Orencia is a logical choice for those patients failing anti-TNF therapy. It is sold by Bristol-Myers Squibb.

–TNFR2-Fc: 

Enbrel (entanercept): Amgen markers Enbrel® which is a fusion protein of the soluble portiion of human tumor necrosis factor receptor joined with the Fc region of IgG1 as a therapy for rheumatoid arthritis.  US 8,063182 covers the entaercept protein itself and US 8,163,522 covers a method of producing it. The patents do not exprie until 2028/2029. Entanerceipt constitutes a soluble fragment of the 75 KD human tissue TNF receptor that is fused to the hinge, CH2-CH3 region of the H cahin of IgG. The purposted befit of the fusion prtoein is that fusing a receptor with IgG prtoeins yields increased affinity for the TNF antigen. The TNFr:IgG prtoein dimerizes adn therefore displays two copies of the receptor, thus increasing affinity. In addition, the half life of the fusion protein is also purportedly much greater than the TNF receptor alone. 

Other novel treatments which will challenge dominance of TNF blockers such as Centocor’s Remicade (infliximab), Amgen/Wyeth’s Enbrel (etanercept) and Abbott’s Humira (adalimumab) are likely to follow. Rituxan, a B cell targeted chiermic antibody from Cambridge, MA-based Biogen Idec is also now in treals for RA. Another possible RA drug is Chugai’s anti-Il-6 MRA antibody, which is now in phase 3.

5) Antibodies against specific molecules: 

–CD20 antibodies: anti-CD20 MAB (Rituximab) has been shown to effectively reduce B cell numbers and is being evlauted in hclinical trials for pateints with autoimmuen diseases.

-CD22 antibodies:  is a B cell specifi c glycoprotein that first appears intracellularly during the late pro B cell stage of ontogency, with expression shifting to the plasma membrane with B cell meturation until plasma cell differentiation. CD22 deficient mice have hyperactivated B cells and CD22 deficiency is sufficient to predispose to development of high affinity autoantibodies in mice. The development of MABs that block CD22 engagement may have considerable benefit for treatment of autoimmunity (Tuscano, Autoimmunity Reviews 2 (2003) 101-108

–CD200 antibodies: Wang (12/452772) discloses that an anti-CD200 antibody lessened RA conditions in an arthritis animal model (collagen induced arthritis (CIA) mouse model strain from Jackon Labs). Bowdish (WO2007/084321) also discloses that anti-CD200 antibodies can be useful for treating autoimmune disease such as rheumatoid arthritis. Liversidege (US2007/0065438) also dicloses administration of an agonist or antagonist of CD200 such as an antibody that specifically binds to CD200 for treating a disorder such as rheumatoid arthritis. 

 –CD200R antibodies: Gorczynski (US 2005/0048069; US 2005/0107314) diclose that anti-CD200R antiboides reduce symptoms of established RA.  The antiboides bind to and crosslink CD200 receptor which enhances the immune suppression caused by CD200.

–IL-1 antibodies: Joosten (Arthritis & Rheumatism) discloses that anti-IL1 alpha/beta treatment ameliorated both early and full blown collagen-induced arhtritis (CIA), which is a widely used experimental model of polyarthritis.

–TNF-alpha antibodies: such as infliximab and adalimumab have been shown to be very effective in treating RA. (See antibodies and therapeutic applications). The Biosimilars simlandi (adalimumab-ryvk) made by Alvotech and Teva Pharmaceuticals and interchangeable with Humira has also been approved. The biosimilar, a TNF alpha inhibitor was approved to be provided as a single-dose autoinjector delivering 40 mg/0.4 mL, for treating plaque psoriasis, Crohn’s disease, ulcertative colities, rheumatoid arthritis juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, hidradenitis suppurative and uveitis. 

(6) Glucocorticoids: Steroids at dosages equivalent to less than 10 mg of prednisone daily are highly effective for relieving symptoms of RA and can slow joint damage.

(7) IVIG: Weisbart (US2002/0098182) disclsoes  treating immune mediated diseases such as RA by oral administration of Cohn Fraction II+III.

Alternative Medicine and Food Products as Treatment Options

(1) Green tea, called EGCG, reportedly inhibits production of several immune system molecules involved in inflammation and joint damage. It inhibits proudction of IL-6 and prostaglandin E2, the inflammatory products found in the connective tissue of people with rheumatoid arthritis. In one study by Dr. Ahmed, synovial fibroblasts (cells that form a lining of synovial tissue surrounding the capsule of the joints) were isolated from the joints of patients suffering from rheumatoid arthritis. EGCG was able to block IL-1bettas ability (the cells were stimulated with IL-1betta) to produce proteins and enzymes that infiltrate the joints of persons with rheumatoid arthritis.

See Medicine.net 

Ankylosing spondylitis (AS)

AS is an inflammatory arthritis and enthesitis involving the spine and peripheral joints. About 350,000 pople in the US ahve AS. Traditional therapies, including disease modifying antirheumatic drugs, nonsteroidal antiinflammoatry drugs and corticosteroids do not adequately control diase activity in most patients.  Etanercept (TNF receptor) has been shwon to substantially reduce diase activity. (Davis, Arthritis & Rheumatism, 48(11), 2003, pp. 3230-3236).

Osteoarthritis

Osteoarthritis is a type of arthritis caused by the breakdown and eventual loss of cartilage of one or more joints. Among the 100 different types of arthritis it is the most common, affecting more than 20 million people in the US. Osteoarthritis occurs more frequently with increasing age. Before age 45, it occurs more frequently in males. After 55, it occurs more frequently in females. Osteoarthritis commonly affects the hands, feet, spine, and large weight bearing joints such as the hips and knees.

Mechanisms of the Disease: The disease mechanisms active in OA are unclear, but changes in the biochemical and biomechanical proeprties of joint carilage, changes in chondrocyte matrix synthesis, and finally, a gradual destruction of the matrix are characteristic of the disease process. The breakdown of articular cartilage in OA is mediated by various enzymes such as metalloproteinases, plasmin and cathepsin, which are in turn stimulated by various factors that can also act as inflammatory mediators.

–Interleukin-1 (IL-1) has been implicated as a mediator of anabolic and catabolic processes in the progression of osteoarthritis (OA). (Shamji, Arthritis & Rheumatism 56(1), 2007, pp. 3650-3661). 

Symptoms: The diagnostic criteria for OA is based on the clinical presentation and decreased joint space. Since this depends on the actual destruction of joint cartilage, it will be made only late in the disease. Unfortunately, we lack routine methods to diagnose “preOA” or ongoing disease.

Treatments:

–Inhibitors of Aggrecanases: Administration of antibodies to specific sites where aggrecan is cleaved by aggrecanases has been proposed as a potential therapeutic method (US 5427954).

–Recombinant IL-1Ra: has been approved as treatment for RA. Signaling through the IL-1 receptor is modulated by IL-1 receptor antagonist (IL-1Ra) which competitively antagonizes the binding of IL-1. 

(Shamji, Arthritis & Rheumatism 56(1), 2007, pp. 3650-3661) discloses development of IL-1Ra – elastin-like polypeptide (ELP) domain fusion proteins. ELPs are genetically engineered polypentapeptide biopolymers with structure homology to mammalian elastin. They are composed of pentapeptide repeats of Val-Pro-Gly-X-Gly and are soluble below their characteristic transition temperature and undergo an abrupt inverse temeprature phase transition to form micron-sized multiparticle aggregates upon heating. Introduction of the thermally responsive ELP tag on the end of IL-1Ra may yield high local doses and provides sustained release and lower systemic exposure for teht reatment of OA. 

–Diet/Health Factors:  Omega 3 supplements have been reported to be beneficial for arthritis. Loose weight because puts extra weight on your bones. Avoid saturated fats. Antioxidants such as vitamin C may help. Certain food groups like citrus foods, foods with selenium, seafood (crabs, Brazil nuts, weat germ (can sprinkle on anything), caratenes (bright orange, dark green vegetables). (hot chillis peppers, corn, squase). Bioflavonoids can also suppress enzymes that eroid cartelgeg (onions, deep colored grapes, berries and cherries). Spices may be beneficial too.

–NSAIDs (Non-steroidal anti-inflmaatory drugs): 

—-diclofenac:  Pennsaid 

A number of patents such as US 8,252,838 and 8,546450 are directed to formulations and methods of using diclofenac. The patents are also listed in the FDA Approved Drug Proudcts With Therapeutic Equivlaence Evaluations (“Orange Book”).

Pennsaid 2% above is a nonsteroidal anti-finlammatory drug (NSAID) and the first FDA approved twice daily topical diclofenac sodium formulation for the treatment of pain of osteoarthritis fo the knees. The drug includes diclofenac sodium as the active ingredient, diemthyl sufloxide (DMSO) as a penetration enhancer, ethanol as a solvent which dissolves teh active ingredient for adsorption of the drug into the skin, and propylene glycol as a solvent/penetration enhancer, hydroxypropyl cellulose (HPC) as a thickening agent, glycerin as a humectant that hold water onto the skin and water as a solvent. 

Juvenile Rheumatoid Arthritis (JRA): 

JVA is the most common cause of disability in children. Its etiology is unkown, although circulating autoanitbodies are common. For example, studies have shown a highly significant association between early-onset pauciarticular JRA and circualting antibodies to the 43-kDa nuclear protein DEK (Adams, Arthritis Research & Therapy, 5(4), 2002. It is possible that the DEK antigen may be involved in the etiopathogenesis of JRA, perhaps by activation of CD8+ T cells (Ferero, Human Immunology 39, 443-450 (1998). However, one studies concludes that anti-DEK autoanitobdies are less specific for JRA than previously believed (Dong, Arthritis & Rheumatism, 43(1), 2000, pp. 85-93).

Psoriatic arthritis: 

Psoriatic arthritis is a chronic inflammatory joint disorder that affects 5 to 8% of people with psoriasis. A significant percentage of these people develop progressive destructive disease. About 25% of psoriasis patients with joint inflammation develop symmetric joint inflammation resembling the joint inflammation manifestations of rheumatoid arthritis RA. Although the disease resembles RA, it does not produce the antibodies characteristic of RA. Psoriasis (a skin condition causing flare-ups of red, scaly rashes and thickened, pitted nails) may precede or follow the joint inflammation. The arthritis usually affects joints of the fingers and toes, although other joints, including the hips and spine, are often affected as well.