# Targeted DOK7 gene therapy for Congenital Myasthenic Syndromes

> **NIH NIH R44** · AMPLO BIOTECHNOLOGY, INC. · 2021 · $253,925

## Abstract

PROJECT SUMMARY
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, β2-adrenergic receptor
agonists, which provide suboptimal symptom management for some patients. Moreover, prolonged exposure
to β2-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.

## Key facts

- **NIH application ID:** 10321309
- **Project number:** 1R44NS124351-01
- **Recipient organization:** AMPLO BIOTECHNOLOGY, INC.
- **Principal Investigator:** Patricio Sepulveda
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $253,925
- **Award type:** 1
- **Project period:** 2021-09-15 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10321309

## Citation

> US National Institutes of Health, RePORTER application 10321309, Targeted DOK7 gene therapy for Congenital Myasthenic Syndromes (1R44NS124351-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10321309. Licensed CC0.

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