# Project 1: Translational and pre-clinical studies of muscular dystrophy gene therapy using AAV

> **NIH NIH P50** · UNIVERSITY OF WASHINGTON · 2021 · $642,962

## Abstract

This translational research project is designed to improve current AAV vector mediated dystrophin gene
therapy methods, to adapt those methods for dominant muscular dystrophies, and to enhance our clinical
infrastructure to facilitate participation in future AAV gene therapy trials. Our previous efforts have involved
years of collaborative studies that have significantly advanced methods and approaches for gene therapy of
DMD. They have also led to approaches to begin harnessing inhibitory RNAi and gene targeting to abrogate
gene expression in dominantly inherited muscular dystrophies. We have also developed approaches for
systemic gene delivery using AAV vectors, and have made important advances in the study of muscle gene
regulation that enable muscle-restricted gene expression and immune evasion following AAV vector delivery.
The AAV/micro-dystrophin approaches are far enough along that they are entering human clinical trials to
assess safety, and primarily in skeletal muscles, efficacy. The micro-clones, however, are still not fully
functional and show reduced activity in cardiac muscles compared with skeletal muscles. The gene therapy
approaches for FSHD have been slowed by a lack of good animal models and difficulties in adapting RNAi to
AAV. Nonetheless these methods are far enough along that it is reasonable and imperative to enhance their
application for optimal gene therapy of many different types of muscular dystrophy. Consequently, our specific
aims focus on several of the key limitations of current approaches to gene therapy for DMD and FSHD. For
DMD, we focus on enhancing approaches that will functionally target both skeletal and cardiac muscles. We
will develop improved gene regulatory cassettes active in all striated muscles, as well as exclusively in skeletal
or cardiac muscle. Novel mini-and micro-dystrophins with enhanced function in striated muscles will be
designed and screened in multiple test systems. We will also test a promising dual vector strategy, combining
dystrophin replacement (structural-based therapy) with enhanced contractile performance via increased
ribonucleotide reductase (contractile augmentation therapy) to improve cardiac performance. Our second area
of focus is to build upon previous AAV studies for DMD and on mouse model development for FSHD to adapt
AAV methods for gene therapy of FSHD. These studies will include analysis of patterns of Dux4 expression in
muscle cells. They will also focus on developing and testing AAV vector mediated tissue-specific expression of
RNAi hairpins targeting Dux4 mRNA in the context of low level mRNA expression in our AAV-DUX4 mouse
model. Finally, we plan to develop patient databases and natural history data focused on cardiac function with
colleagues at the MDA clinics in Seattle. We will gather and organize data from ongoing cardiac imaging
studies, functional readouts, natural history data and mutational spectra in the DMD patient populations served
by the Seattle clini...

## Key facts

- **NIH application ID:** 10248345
- **Project number:** 5P50AR065139-08
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** JEFFREY S CHAMBERLAIN
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $642,962
- **Award type:** 5
- **Project period:** 2014-05-07 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10248345

## Citation

> US National Institutes of Health, RePORTER application 10248345, Project 1: Translational and pre-clinical studies of muscular dystrophy gene therapy using AAV (5P50AR065139-08). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10248345. Licensed CC0.

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