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.