Congenital Myasthenic Syndromes (CMS) are a group of genetically and phenotypically heterogeneous, neuromuscular transmission disorders characterized by muscle weakness (myasthenia) that worsens with physical exertion. DoK-7 (Downstream of tyrosine kinase 7) is a key regulator of neuromuscular junction (NMJ) formation. Homozygous loss-of or reduction of-function mutations in the human DOK7 gene underlie a limb-girdle type of CMS characterized by NMJs that are about half the normal size. DoK-7 CMS is an orphan disease estimated to affect 3,600 people worldwide. Patients with DoK-7 CMS have a decreased Quality of Life (QoL) due to exercise intolerance, dependency on intermittent respiratory support, and/or tube feeding by adulthood (2/3 of the patients). Moreover, about half of the patients will need a wheelchair for ambulation, and the other half will require walking aids. No cure nor standardized treatment has been yet developed for DoK-7 CMS. While forms of CMS are managed through the administration of acetylcholine (AChE) inhibitors, DoK-7 CMS is refractory and can deteriorate if treated with AChE inhibitors. Symptoms ameliorations for DoK-7 CMS is achieved by recurrent administration of Ephedrine and Albuterol, ß2-adrenergic receptor agonists, which provide suboptimal symptom management for some patients. Moreover, prolonged exposure to ß2-adrenergic receptor can cause tachycardia cardiac ischemia, heart failure, cardiomyopathy, and increased inflammatory response. Amplo Biotechnology is developing AMP-101, the first gene therapy product for DoK-7 CMS. The treatment is based on a recombinant adeno-associated virus serotype 9 (AAV9) vector carrying the human DOK7 gene. Preliminary results in a DoK-7 CMS mouse model show that AMP-101 can enlarge NMJs, improve motor function, and extend the very limited (20 days after birth) life span of DoK- 7 CMS mice to the level of WT controls. The new product will enable a shift in the current clinical practice from chronic administration of drugs to alleviate symptoms to a one-off treatment, administered through a single intravenous injection. The solution will allow physicians to treat the entire affected population, curing adult disease, and stopping disease progression in children. The goal of this SBIR Fast-Track project is to validate the efficacy and safety of using AMP-101 for DoK-7 CMS. Amplo will use Phase I activities to perform a pre-clinical dose-finding and safety study in DoK-7 CMS mice. The outcome of Phase I activities will be used to direct pivotal DMPK/ADME and toxicology studies in non-human primates (NHP) in Phase II, when manufacturing, quality, and stability procedures will also be defined. The experimental plan proposed has been validated by the FDA in a recent pre-IND query and an IND application will be submitted at the end of the project.
Public Health Relevance Statement: NARRATIVE DoK-7 congenital myasthenic syndrome (DoK-7 CMS) is a rare neuromuscular disorder with no cure associated with limb-girdle pattern of weakness, choking spells, respiratory insufficiency, severe scoliosis. This project aims to validate the safety and efficacy of a new gene therapy product for DoK-7 CMS able to shift current clinical practice from chronic administration of drugs to alleviate symptoms to a one-off, non- pharmacological treatment, administered through a single intravenous injection. The project is expected to unveil important insights on the mechanism of action of Neuromuscular Junction formation ultimately applicable to other neuromuscular diseases.
Project Terms: Acetylcholine; Acetylcholinesterase Inhibitors; acetylcholineesterase inhibition; acetylcholineesterase inhibitor; beta-2 Adrenergic Receptors; Beta-2 Adrenoceptor; Catecholamine Receptor; ß-2 Adrenoceptor; ß2 Adrenergic Receptor; Adrenergic Agonists; Adrenergic Receptor Agonist; Adrenomimetics; Adult; 21+ years old; Adult Human; adulthood; Affect; Albuterol; Proventil; Salbutamol; Ventolin; inhibitor; inhibitor/antagonist; Respiratory Aspiration; Respiratory Inspiration; inspiration; Breathing; Assay; Bioassay; Biologic Assays; Biological Assay; Biotech; Biotechnology; Parturition; Birth; Western Blotting; Western Immunoblotting; protein blotting; Child; 0-11 years old; Child Youth; Children (0-21); youngster; Choking; Clinical Trials; Cytomegalovirus; CMV; HCMV; Salivary Gland Viruses; cytomegalovirus group; Disease; Disorder; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Engineering; Ephedrine; Exertion; Limb structure; Extremities; Limbs; Non-Trunk; gene therapy; DNA Therapy; Gene Transfer Clinical; Genetic Intervention; gene-based therapy; genetic therapy; genomic therapy; Genes; Goals; Health; Heart failure; cardiac failure; Human; Modern Man; intravenous injection; Longevity; Length of Life; life span; lifespan; Mus; Mice; Mice Mammals; Murine; Muscle; Muscle Tissue; muscular; Mutation; Genetic Alteration; Genetic Change; Genetic defect; genome mutation; Neurology; Neuromuscular Diseases; myoneural disorder; neuromuscular degenerative disorder; neuromuscular disorder; Neuromuscular Junction; Myoneural Junction; Patients; Pharmacology; Phenotype; Physicians; Production; Protein Tyrosine Kinase; EPH- and ELK-Related Tyrosine Kinase; EPH-and ELK-Related Kinase; Ephrin Type-A Receptor 8; Ephrin Type-A Receptor 8 Precursor; Protein Tyrosine Kinase EEK; Tyrosine Kinase; Tyrosine-Protein Kinase Receptor EEK; Tyrosine-Specific Protein Kinase; Tyrosylprotein Kinase; hydroxyaryl protein kinase; tyrosyl protein kinase; Quality of life; QOL; Adrenergic Receptor; Adrenoceptors; Epinephrine Receptors; adenoreceptor; Recurrence; Recurrent; Respiratory Insufficiency; lung insufficiency; Running; Safety; scoliosis; Serotyping; Ships; Signal Transduction; Cell Communication and Signaling; Cell Signaling; Intracellular Communication and Signaling; Signal Transduction Systems; Signaling; biological signal transduction; Standardization; Syndrome; Tachycardia; Testing; Time; Tokyo; Toxicology; Universities; Wheelchairs; Wheel Chairs; mobile assistance device; mobile assistance system; mobile assistive device; mobile assistive system; Walking; Enteral Feeding; enteric feeding; feeding tube; gastric feeding; tube feeding; Myocardial Ischemia; Ischemic Heart; Ischemic Heart Disease; Ischemic myocardium; cardiac ischemia; coronary ischemia; heart ischemia; myocardial ischemia/hypoxia; myocardium ischemia; Muscular Weakness; Muscle Weakness; base; improved; Procedures; Lateral; Chronic; Clinical; Refractory; Phase; Biological; Ensure; Evaluation; pediatric; Childhood; insight; non-human primate; nonhuman primate; Disease Progression; Collaborations; Exposure to; Inflammatory; Disorder Management; Disease Management; programs; Hereditary; Inherited; Dependence; Clinic; Pattern; Spinal; respiratory; Degenerative Neurologic Diseases; Degenerative Neurologic Disorders; Nervous System Degenerative Diseases; Neural Degenerative Diseases; Neural degenerative Disorders; Neurodegenerative Diseases; Neurologic Degenerative Conditions; degenerative diseases of motor and sensory neurons; degenerative neurological diseases; neurodegenerative illness; Neurodegenerative Disorders; spelling; Toxicities; Toxic effect; Orphan Disease; Rare Disorder; orphan disorder; Rare Diseases; novel; Congenital Myasthenia Gravis; Congenital Myasthenic Syndromes; Neuromuscular Junction Disorders; Neuromuscular Transmission Disorders; Neuromuscular Junction Diseases; response; assay development; Myocardial Diseases; Myocardial Disorder; Myocardiopathies; myocardium disease; myocardium disorder; Cardiomyopathies; Intervention Strategies; interventional strategy; Intervention; Myasthenia; Inflammatory Response; Dose; Defect; Symptoms; SBIR; Small Business Innovation Research; Small Business Innovation Research Grant; Validation; Viral Vector; Transmission; transmission process; Preparation; manage symptom; symptom management; safety study; preclinical; pre-clinical; pre-clinical study; preclinical study; NINDS; National Institute of Neurological Diseases and Stroke; National Institute of Neurological Disorders and Stroke; vector; feeding; Advanced Development; design; designing; efficacy evaluation; efficacy analysis; efficacy assessment; efficacy examination; evaluate efficacy; examine efficacy; Biodistribution; Outcome; Population; innovation; innovate; innovative; Recombinant adeno-associated virus (rAAV); Recombinant adeno-associated virus; rAAV; recombinant AAV; mouse model; murine model; disease-causing mutation; preclinical efficacy; pre-clinical efficacy; clinical practice; motor function improvement; improved motor function; exercise intolerance; reduce symptoms; alleviate symptom; ameliorating symptom; decrease symptom; fewer symptoms; relieves symptoms; symptom alleviation; symptom reduction; symptom relief; experimental study; experiment; experimental research; efficacy study; clinical development; preclinical development; pre-clinical development; recruit; pharmacokinetics and pharmacodynamics; PK/PD; efficacy validation; validate efficacy
