Advances in gene therapies for limb-girdle muscular dystrophies

Abstract

Limb-girdle muscular dystrophies (LGMDs) comprise a heterogeneous group of genetically determined disorders in which degeneration of the skeletal muscle is prominent. As no efficient pharmacological therapies exist that are able to reverse the course of these diseases, alternative regenerative therapies based on cell transfer or gene transfer approaches have been developed. These latter therapies will be the topic of this mini-review. To date, recombinant adeno-associated viral vectors have been reported as the best available gene transfer vectors for gene therapies targeting skeletal muscle tissue, due to their high tropism for this tissue, long-term stability, and low immunogenicity, among other features. However, the fact that these vectors cannot package large gene sizes represents a hurdle for the treatment of LGMDs caused by defects in large genes. Preclinical studies based on the transfer of disease-causing genes or muscle regulator genes that could ameliorate the course of the disease have led to a few clinical trials in which safety and efficacy studies are currently being performed. However, important barriers such as difficulties in delivering the viral vectors through all the affected skeletal muscles, the degenerative stage of the muscle at the time of treatment, and the potential immune response against the protein encoded by the transferred gene need to be overcome in order to maximize the efficacy of the therapies and prevent the development of the diseases.