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Braun. J Transl Genet Genom. 2025;9:35-47 Journal of Translational
DOI: 10.20517/jtgg.2024.79
Genetics and Genomics

Review Open Access

Duchenne muscular dystrophy, one of the most
complicated diseases for gene therapy

Serge Braun

Scientific Department, AFM-Telethon/Genethon, EVRY 91002, France.
Correspondence to: Dr. Serge Braun, AFM-Telethon/Genethon, 1 rue de l’Internationale, Evry 91002, France. E-mail:
sbraun@afm-telethon.fr
How to cite this article: Braun S. Duchenne muscular dystrophy, one of the most complicated diseases for gene therapy. J Transl
Genet Genom. 2025;9:35-47. https://dx.doi.org/10.20517/jtgg.2024.79
Received: 10 Oct 2024 First Decision: 5 Dec 2024 Revised: 9 Jan 2025 Accepted: 17 Jan 2025 Published: 26 Jan 2025

Academic Editors: Sanjay Gupta, Corrado Italo Angelini Copy Editor: Ping Zhang Production Editor: Ping Zhang

Abstract
Gene therapy for Duchenne muscular dystrophy (DMD) is hindered by many pitfalls related in particular to the
limitations of current technologies, the specificities of muscle and cardiac targets, and the disease itself, a chronic,
multisystem, dystrophic and inflammatory disorder. Following RNA-based therapies, DNA gene transfer, mainly
based on adeno-associated viral vectors, is now able to deliver therapeutic genetic sequences on a massive scale,
and the first antisense and adeno-associated virus (AAV)-microdystrophin gene products are now reaching the
marketing stage in Europe and/or in the US. However, only a subset of patients are eligible for those therapies.
Many questions remain, such as the duration of the therapeutic effect, the burden of high doses of vectors, and the
immunogenicity of viral capsids and therapeutic proteins, in the context of a disease-related inflammatory
background. Evaluations of these treatments by the different biotech, pharma or non-for-profit sponsors also come
up against the great clinical heterogeneity of patients. This review summarizes the significant progress made over
the past three decades to optimize both the efficacy and safety of DMD gene therapies, as well as the remaining
challenges, short-term prospects, and future directions such as more targeted vectors and combination therapies.

Keywords: AAV, antisense oligonucleotide (ASO), DMD, microdystrophin, immune rejection, duchenne

INTRODUCTION: NUMEROUS HURDLES TO OVERCOME
Duchenne muscular dystrophy (DMD) is certainly one of the most complex diseases to address with gene

© The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution 4.0
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