Challenges in developing gene therapy against Duchenne muscular dystrophy

Duchenne muscular dystrophy is a progressive X-linked recessive neuromuscular disorder resulting from pathogenic mutations in the DMD gene, which codes dystrophin. It is one of the essential structural proteins of muscle cells that maintains the integrity of cross-striated muscles. Duchenne muscular dystrophy causes progressive muscular weakness and, as a consequence, reduces life expectancy due to respiratory failure and/or heart failure. Glucocorticoids are considered the standard of care in Duchenne muscular dystrophy, although they are not highly effective and may lead to numerous adverse effects. For decades, many studies have been focused on finding an effective therapy for Duchenne muscular dystrophy; however, no etiology-oriented product is currently available for patients with Duchenne muscular dystrophy. That being said, the latest studies demonstrate that promising effective gene therapy for Duchenne muscular dystrophy is possible in the near future. The ongoing studies include approaches such as replacement therapy with shortened dystrophin forms and genome editing. Despite high efficacy of the approaches in vitro and in animal models, there is a number of challenges when it comes to treating human patients with Duchenne muscular dystrophy. The first challenge is the gene size — DMD is one of the largest genes, which makes it difficult to load it into viral vectors for delivery. Second, Duchenne muscular dystrophy is caused by over 7000 mutations, so creating universal gene therapies applicable to wide patient populations is problematic. Besides, low efficacy of genetic structure delivery and immune responses — both to the transgene and the viral vector — are a concern. Moreover, long-term sequelae of dystrophin deficiency could persist even if the protein expression is restored. The ongoing studies offer strategies to overcome the limitations above. This review aims to discuss the current challenges, the solutions to which may become a breakthrough in gene therapy for Duchenne muscular dystrophy and other hereditary diseases.