Duchenne Muscular Dystrophy Gene Therapy in 2023: Status, Perspective, and Beyond

Abstract

Duchenne muscular dystrophy (DMD) was named more than 150 years ago. About four decades ago, the DMD gene was discovered, and the reading frame shift was determined as the genetic underpinning. These pivotal findings significantly changed the landscape of DMD therapy development. Restoration of dystrophin expression with gene therapy became a primary focus. Investment in gene therapy has led to the approval of exon skipping by regulatory agencies, multiple clinical trials of systemic microdystrophin therapy using adeno-associated virus vectors, and revolutionary genome editing therapy using the CRISPR technology. However, many important issues surfaced during the clinical translation of DMD gene therapy (such as low efficiency of exon skipping, immune toxicity-induced serious adverse events, and patient death). In this issue of Human Gene Therapy, several research articles highlighted some of the latest developments in DMD gene therapy. Importantly, a collection of articles from experts in the field reviewed the progress, major challenges, and future directions of DMD gene therapy. These insightful discussions have significant implications for gene therapy of other neuromuscular diseases.

Keywords: CRISPR editing; Duchenne muscular dystrophy (DMD); adeno-associated virus (AAV); exon skipping; gene therapy; microdystrophin.

Figure 1.

Development of dystrophin restoration gene therapy for Duchenne muscular dystrophy. (A) Affected boys are usually diagnosed between 2 and 5 years of age and lose ambulance in their early teens. The photographs show a patient at the early stage of the disease (left) and when wheelchair bound (right). Courtesy of Jen Portnoy at Hope for Javier. (B) Milestones in discovering the disease, the disease gene, and the genetic mechanism underlying the disease. (C) Milestones and major challenges in developing exon-skipping, microdystrophin, and CRISPR editing therapies.