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ABSTRACT
Introduction: The development of adeno-associated virus (AAV) vectors as safe vehicles for in vivo delivery of therapeutic genes has been a major milestone in the advancement of gene therapy, enabling a promising strategy for ameliorating a wide range of diseases, including Duchenne muscular dystrophy (DMD).
Areas covered: Based on experience with the development of a gene transfer therapy agent for DMD, we discuss ways in which gene therapy for rare disease challenges traditional clinical development paradigms, and recommend a step-wise approach for design and evaluation to support broader applicability of gene therapy.
Expert opinion: The gene therapy development approach should intentionally design the therapeutic construct and the clinical study to systematically evaluate agent delivery, safety, and efficacy. Rigorous preclinical work is essential for establishing an effective gene delivery platform and determining the efficacious dose. Clinical studies should thoroughly evaluate transduction, on-target transgene expression at the tissue and cellular level, and functional efficacy.
Article Highlights
The development of adeno-associated virus (AAV) vectors as vehicles for in vivo delivery of target genes has been a major milestone in the advancement of gene therapy, emerging as a promising strategy for ameliorating a wide range of diseases, including Duchenne muscular dystrophy (DMD).
Experience from the development of gene transfer therapy for DMD has highlighted unique challenges and critical factors to be considered in the successful development of a gene therapy product.
Rigorous preclinical and clinical study design and thoughtful evaluation of outcomes are necessary for overcoming limitations that potentially preclude broader applicability of gene therapy.
In order to provide meaningful data to patients, families, and clinicians, gene therapy development programs should include step-wise assessment of safety; delivery of the transgene DNA to the target cell; expression of the transgene protein; localization of the transgene protein within intended tissues; transgene function at the cellular level; and impact on disease outcomes.
This box summarizes the key points contained in the article.
Acknowledgments
Medical writing and editorial support was provided by Purvi Kobawala Smith and Marjet Heitzer of Health & Wellness Partners, LLC, Upper Saddle River, NJ, funded by Sarepta Therapeutics, Inc. The authors would like to thank Allison Kreuzer for her contribution to the figures and Ashish Dugar and Jyoti Malhotra for their review and guidance.
Declaration of interest
The authors are employees of Sarepta Therapeutics, Inc, and may have stock options. JR Mendell has received study funding from Sarepta Therapeutics and has a service agreement with Sarepta Therapeutics to provide training on ongoing studies. In addition, he is the co-inventor of AAVrh74.MHCK7.micro-dys technology (patent pending) which is exclusively licensed to Sarepta Therapeutics. LR Rodino-Klapac is an employee of Sarepta Therapeutics, has received grant support from Sarepta Therapeutics and the Parent Project Muscular Dystrophy, as well as financial consideration from Sarepta Therapeutics and the Myonexus Therapeutics (now acquired by Sarepta Therapeutics). In addition, she is the co-inventor of AAVrh74.MHCK7.micro-dys technology (patent pending) which is exclusively licensed to Sarepta Therapeutics. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Reviewer Disclosures
Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.