Targeted DOK7 gene therapy for congenital myasthenic syndromes
Ended Project Grant Awarded Last action
- Award ID
- R44NS124351
- Recipient
-
Amplo Biotechnology Inc. UEI H93DMA2RBMS1
- Awarding agency
-
National Institute of Neurological Disorders and Stroke
National Institutes of Health, Department of Health and Human Services
- Obligated
- $12,739,517
Award facts
- Assistance listing
- 93.853 Extramural Research Programs in the Neurosciences and Neurological Disorders
- Completion date
- Originally
- Funding
-
- $12,485,592.00 Federal
- $253,925.00 Non-federal
- Place of performance
- Maryland, USA
Award details come from USAspending.gov.
Description
- Abstract
- 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.
Transactions
| Action | Federal | Non-federal | Date |
|---|---|---|---|
| Amendment | $0 | $0 | |
| Amendment | $2,999,358 | $0 | |
| Amendment | $2,999,358 | $0 | |
| Amendment | $144,102 | $0 | |
| Amendment | $0 | $0 | |
| Amendment | $0 | $0 | |
| Amendment | $0 | $0 | |
| Amendment | $0 | $0 | |
| Amendment | $0 | $0 | |
| Amendment | $0 | $0 | |
| Amendment | $1,458,731 | $0 | |
| Amendment | $1,458,731 | $0 | |
| Amendment | $1,458,731 | $0 | |
| Amendment | $1,458,731 | $0 | |
| Amendment | $253,925 | $0 | |
| Original award | $253,925 | $253,925 |
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Quick answers
Who received award R44NS124351?
R44NS124351 was awarded to Amplo Biotechnology Inc. by National Institute of Neurological Disorders and Stroke (National Institutes of Health) on September 15, 2021.
How much is award R44NS124351 worth?
$12,739,517 has been obligated on R44NS124351: $12,485,592 in federal funding and $253,925 in non-federal funding.
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