Secreted acid sphingomyelinase as a potential gene therapy for limb girdle muscular dystrophy 2B

Efficient sarcolemmal repair is required for muscle cell survival, with deficits in this process leading to muscle degeneration. Lack of the sarcolemmal protein dysferlin impairs sarcolemmal repair by reducing secretion of the enzyme acid sphingomyelinase (ASM), and causes limb girdle muscular dystrophy 2B (LGMD2B). The large size of the dysferlin gene poses a challenge for LGMD2B gene therapy efforts aimed at restoring dysferlin expression in skeletal muscle fibers. Here, we present an alternative gene therapy approach targeting reduced ASM secretion, the consequence of dysferlin deficit. We showed that the bulk endocytic ability is compromised in LGMD2B patient cells, which was addressed by extracellularly treating cells with ASM. Expression of secreted human ASM (hASM) using a liver-specific adeno-associated virus (AAV) vector restored membrane repair capacity of patient cells to healthy levels. A single in vivo dose of hASM-AAV in the LGMD2B mouse model restored myofiber repair capacity, enabling efficient recovery of myofibers from focal or lengthening contraction- induced injury. hASM-AAV treatment was safe, attenuated fibro-fatty muscle degeneration, increased myofiber size, and restored muscle strength, similar to dysferlin gene therapy. These findings elucidate the role of ASM in dysferlin-mediated plasma membrane repair and to our knowledge offer the first non-muscle-targeted gene therapy for LGMD2B.

Automated summary

Efficient sarcolemmal repair is crucial for muscle cell survival. This study presents a novel gene therapy approach for limb girdle muscular dystrophy 2B (LGMD2B) targeting reduced secretion of acid sphingomyelinase (ASM). Treatment with liver-specific adeno-associated virus (AAV) vector expressing human ASM (hASM) restored membrane repair capacity and improved muscle strength in patient cells and a mouse model. This non-muscle-targeted gene therapy could attenuate muscle degeneration and provide a potential treatment for LGMD2B.