Microdystrophin Expression as a Surrogate Endpoint for Duchenne Muscular Dystrophy Clinical Trials

Jeffrey S. Chamberlain, Melissa Robb, Serge Braun, Kristy J. Brown, Olivier Danos, Annie Ganot, Pedro Gonzalez-Alegre, Nina Hunter, Craig McDonald, Carl Morris, Mark Tobolowsky, Kathryn R. Wagner, Olivia Ziolkowski, Dongsheng Duan

Research output: Contribution to journalArticlepeer-review

Abstract

Duchenne muscular dystrophy (DMD) is a serious, rare genetic disease, affecting primarily boys. It is caused by mutations in the DMD gene and is characterized by progressive muscle degeneration that results in loss of function and early death due to respiratory and/or cardiac failure. Although limited treatment options are available, some for only small subsets of the patient population, DMD remains a disease with large unmet medical needs. The adeno-Associated virus (AAV) vector is the leading gene delivery system for addressing genetic neuromuscular diseases. Since the gene encoding the full-length dystrophin protein exceeds the packaging capacity of a single AAV vector, gene replacement therapy based on AAV-delivery of shortened, yet, functional microdystrophin genes has emerged as a promising treatment. This article seeks to explain the rationale for use of the accelerated approval pathway to advance AAV microdystrophin gene therapy for DMD. Specifically, we provide support for the use of microdystrophin expression as a surrogate endpoint that could be used in clinical trials to support accelerated approval.

Original languageEnglish (US)
Pages (from-to)404-415
Number of pages12
JournalHuman gene therapy
Volume34
Issue number9-10
DOIs
StatePublished - May 1 2023
Externally publishedYes

Keywords

  • AAV vector
  • Duchenne muscular dystrophy
  • gene therapy
  • microdystrophin

ASJC Scopus subject areas

  • Genetics
  • Molecular Medicine
  • Molecular Biology

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