Introduction:
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:
Acute deliriumis 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 degrees 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.
Attention Deficit Disorder (ADD or ADHD):
Attention Deficit Disorder (ADD), more formally known as Attention-Deficit/Hyperactivity Disorder (ADHD), is a neurodevelopmental disorder. This means it affects the way the brain develops and functions, particularly in areas related to attention, impulse control, and sometimes hyperactivity. It’s usually first diagnosed in childhood but can persist into adulthood.
Treatments:
—CONCERTA (methylphenidate HCL – J&J): belongs to a class of medications called stimulants. Concerta works by increasing levels in your brain of two neurotransmitters (chemical messengers) called norepinephrine and dopamine. Increasing these neurotransmitter levels helps to stimulate your brain, which can improve the symptoms of ADHD. Each CONCERTA extended-release tablet contains 18 mg, 27 mg, 36 mg or 54 mg of methylphenidate hydrochloride as the active ingredient.
Amyotrophic lateral sclerosis (ALS; also known as Lou Gehrig’s disease):
Introduction: 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. A
DiagnosisSymptoms: LS leads to progressive muscle weakness and atrophy through the body, ultimately leading to paralysis and death within 3-5 years of symptom onset. 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.
Two forms of ALS have been described: one is sporadic ALS (SALS), which is the most common form of ALS in the US and accounts for 90-95 of all caes diagnosed; the other is familiar ALS (FALS), which occurs in a family lineage mainly with a dominant ineritance and only accounts for about 5-10% of cases in the US. SALS and FALS are clinically indistiguishable.
Etiology/Causes:
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.
–-Familial ALS: More than a dozen genes associated with ALS have been discovered, including SOD-1, TDP-43, FUS, ANG, ATXN2, CCP, OPTN. However, the exact mechanisms of motor neuron degeneration are still elusive.
Dominant mutations in the Cu-Zn superoxide dismutates 1 (SOD1) gene accounts for about 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).
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.
Biomarkers:
–TDP43 or SOD are biomarkers for ALS
Treatment: 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.
–Riluzole: is an FDA approved drug which antagnoizes the glutamate response to reduct the pathological development of ALS. However, only about 3 month lefe span exapnsion for ALS patients int he ealry stages has beenr eported.
–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.
HD is an autosomal dominant degeenrative motor disorder that manifests itself with movement dysfunction. It is casued by CAG repeats in the Huntingtin (HTT)gene. When they are more than 36 years old, the mutant HTT protein (mHTT) froms inclusions that compromise brain cell functions. (Venero, “Galectin-3, a rising star in modulating microglia activaiton under conditions of neurodegeneration” (2022)
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 mutations 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 sequence of three 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 disease, 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.
Microglial activation:
Studies have suggested that irregular activaiton of microglia contributes to the pathogenesis of HD. As in other neruodegenerative and neuroinflammatory disorders, Gal-3 has been described to play an essential role in brain inflammation assocaited with HD. (Venero, “Galectin-3, a rising star in modulating microglia activaiton under conditions of neurodegeneration” (2022)
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 (See outline)
Other Microogranisms which cause Neurological Disease
Tetanus: is a neuromuscualr disease which is caused 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.
Transverse myelitis: is a neurological disorder caused by inflammation of the spinal cord, leading to damage to the protective covering (myelin sheath) around nerve cells. This inflammation can disrupt communication between the spinal cord and the rest of the body, causing symptoms like pain, weakness, paralysis, and bladder or bowel control problems.
Transverse myelitis is a relatively rare disease. It occurs most often in children ages 10 to 19 and in adults ages 30 to 39. But it can happen at any age, and to any gender or race. Transverse myelitis can also be a warning sign of multiple sclerosis. But this is rare. Since some people with transverse myelitis have autoimmune diseases, such as lupus, some healthcare providers believe that transverse myelitis may also be an autoimmune disease. Finally, some cancers can trigger an immune response that leads to transverse myelitis.
No effective cure currently exists for transverse myelitis. But there are treatments to prevent or reduce permanent neurological problems. Treatments focus on relieving the inflammation and or infection that causes the symptoms. Some people might need to be hospitalized at first if the symptoms are bad enough. High doses of steroids are used to suppress the activity of the immune system and to decrease swelling and inflammation. Your healthcare provider may also recommend pain-relieving medicines like ibuprofen or acetaminophen, immune-suppressing medicines, and specific medicines that target nerve pain.
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.
Menkes disease is a neurodegenerative disorder caused by a genetic defect that impairs a child’s ability to absorb copper. The disease is characterized by seizures, failure to gain weight and grow, developmental delays, and intellectual disability. It leads to abnormalities of the vascular system, bladder, bowel, bones, muscles, and nervous system. Children with classical Menkes (90% of those with the disease) begin to develop symptoms in infancy and typically do not live past three years. It affects approximately one in every 100,000-250,000 live births worldwide and is more common in boys.
–Zycubo is a copper replacement therapy given by subcutaneous injection. It delivers copper in a form that bypasses the genetic defect in intestinal absorption, allowing the body to better use the mineral. The FDA evaluated Zycubo in two open-label, single-arm clinical trials in pediatric patients treated for up to three years. Overall survival was assessed by comparing treated patients to untreated patients from contemporaneous external control groups. The analysis included 66 treated patients and 17 untreated patients, most of whom were from the United States.
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.