# Controllable base editing therapy for DMD

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2024 · $587,533

## Abstract

PROJECT SUMMARY/ABSTRACT
Duchenne muscular dystrophy (DMD) is a lethal muscle degenerative disease with cardiomyopathy in over 90%
of patients, and heart failure is a leading cause of mortality. DMD patients commonly harbor out-of-frame
mutations which result in complete loss of dystrophin protein. While CRISPR-gene editing has been employed
to delete the mutant exon for restoration of the dystrophin reading frame, this strategy raises potential safety
concerns as it relies on repair of the double strand DNA breaks created by CRISPR/Cas9, which may cause
unwanted large deletion, DNA rearrangement and viral vector integration. Developing novel approaches to
precisely and safely correct the disease-causing mutations in striated muscles is in urgent need to combat DMD.
Recent advances in base editors allow us to explore the feasibility of precise correction of genetic mutations in
animal models of DMD without creating double strand DNA breaks. Our recent studies demonstrate it is highly
efficient to correct a disease-causing point mutation in the striated muscles of a mouse model of DMD using
systemic delivery of adeno-associated virus 9 (AAV9). This paves the way for clinical translation of in vivo base
editing for DMD. However, novel strategies are in urgent need to solve several safety-related issues (e.g. the
accumulation of off-target activities with persistent expression of base editing agents following AAV delivery;
high dose of AAV utilized; host immune responses). Here we propose to develop a novel controllable base
editing system (to reduce accumulation of off-target editing events and exposure of base editor to the host
immune system) delivered in recently engineered myotropic AAV capsids (to increase muscle transduction
efficiency with 10-fold less of AAV as compared to AAV9). The therapeutic efficacy and safety will be extensively
investigated using a newly established DMD rabbit model, which faithfully recapitulates the clinical signs of
muscular dystrophy and cardiomyopathy in human DMD. We will further engineer immune-friendly vectors and
develop a novel immune-modulating strategy to mitigate the host immune responses to the in vivo AAV-delivered
base editing therapy. Completion of the proposed studies will significantly advance our translational efforts to
develop safer precision medicine for DMD.

## Key facts

- **NIH application ID:** 10909367
- **Project number:** 5R01HL170260-02
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Renzhi Han
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $587,533
- **Award type:** 5
- **Project period:** 2023-09-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10909367

## Citation

> US National Institutes of Health, RePORTER application 10909367, Controllable base editing therapy for DMD (5R01HL170260-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10909367. Licensed CC0.

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