# Project 1

> **NIH NIH P50** · UT SOUTHWESTERN MEDICAL CENTER · 2020 · $531,261

## Abstract

Project Summary/Abstract
Duchenne muscular dystrophy (DMD) is an inherited X-linked disease caused by mutations in the gene
encoding dystrophin, a protein required for muscle fiber integrity. The dystrophin gene is one of the largest
human genes and consists of 79 exons. Although there are thousands of individual DMD mutations that have
been identified in humans, these mutations are concentrated in hot spot regions of the dystrophin gene. DMD
affects approximately 1 in 5,000 boys and is characterized by progressive severe muscle weakness and a
shortened lifespan. Despite intense efforts to find cures for DMD through a variety of approaches, including
myoblast transfer, viral delivery of dystrophin, and oligonucleotide-mediated exon skipping, there remains no
cure for this disease. Our approach is to use CRISPR/Cas9 genomic editing to permanently correct DMD by
skipping or reframing the mutant dystrophin exons in postnatal muscle tissue in vivo. We refer to this strategy
as Myoediting. This genome editing approach removes the genetic mutation responsible for the disease,
allowing for permanent correction of muscle structure and function. We deliver the CRISPR/Cas9 components
using an adeno-associated virus-9 (AAV9) delivery system which has been shown to provide robust
expression in skeletal muscle, heart and brain, the major tissues affected in DMD patients. To date, we have
successfully corrected the dystrophin gene mutation in several DMD animal models having mutations in key
hot spot regions of the dystrophin gene. In the previous funding period, we generated several other DMD
animals models covering the remaining human hot spot regions and propose to correct these mutations using
CRISPR/Cas genomic editing. Although we have made much progress using CRISPR/Cas genomic editing to
correct DMD, there remains more work to be done to translate this gene editing therapy to the clinic. The
efficiency of delivering the CRISPR/Cas9 components needs to be optimized and questions remain as to the
durability of dystrophin expression after correction. Furthermore, since muscle fibers have hundreds of nuclei,
we need to understand the occurrence of CRISPR/Cas9 genomic editing at the individual nuclear level. The
long-term goal of this project remains to optimize and adapt CRISPR/Cas9-mediated genome editing to
postnatal muscle and ultimately to leverage this approach to correct DMD mutations in humans. This project
continues to represent a close collaboration between clinicians and basic scientists sharing the common goal
of advancing a new therapeutic strategy to permanently cure DMD.

## Key facts

- **NIH application ID:** 10049128
- **Project number:** 2P50HD087351-06
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** ERIC N Olson
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $531,261
- **Award type:** 2
- **Project period:** 2015-09-15 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10049128

## Citation

> US National Institutes of Health, RePORTER application 10049128, Project 1 (2P50HD087351-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10049128. Licensed CC0.

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