Abstract
Duchenne muscular dystrophy (DMD) is a serious genetic disease that affects muscles, caused by loss-of-function mutations in the DMD gene, which encodes the structural protein dystrophin. The absence of dystrophin leads to destabilization of the dystrophin-associated glycoprotein complex (DAPC), compromises sarcolemmal integrity and trigger progressive muscle fiber degeneration. Current therapeutic strategies focus on restoring dystrophin expression using gene therapy approaches. Adeno-associated virus (AAV) vectors have emerged as the leading delivery platform, thanks to their preferential tropism for muscle tissue, favorable immunogenicity profile, and capacity for sustained transgene expression. Nevertheless, the restricted packaging capacity of AAV (~4.7 kb) constrains transgene design to truncated micro-dystrophin (μDys) constructs. Major challenges include immune responses against the viral capsid and transgene products, as well as limited functional gain observed in patients, that might be due to the lack of key domains in the μDys protein. In this review, we examine the inherent limitations of μDys gene therapy, discuss the rationale for incorporating additional dystrophin domains into therapeutic constructs, and explore the functional and structural domain combinations being investigated to advance next-generation treatments for DMD.
Keywords
Duchenne muscular dystrophy, Adeno-associated virus, Dystrophin, DMD gene