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

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.