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. Keywords: LGMD; gene therapy; muscle regeneration (Published: 25 September 2014) Citation: Advances in Regenerative Biology 2014, 1 : 25048 - http://dx.doi.org/10.3402/arb.v1.25048 Abstract in popular science Limb Girdle Muscular Dystrophies (LGMDs) comprise a wide variety of hereditary diseases that cause muscle wasting of the proximal and limb-girdle skeletal muscles. Each LGMD variant is caused by mutations in a single gene that encodes a muscle-specific protein. Disease severity partially depends on the mutated gene. As a result, some LGMDs are relatively benign whereas other LGMDs involve cardiac dysfunction and can be lethal for the patients in the second or third decade of their lives. Due to the lack of effective pharmacological treatments for LGMDs, innovative therapies are being developed. One of these approaches aims to replace the mutated gene by transferring a healthy copy of the gene, with the help of viral vectors that are able to deliver these genes to the affected muscle tissue. Adeno-Associated Viruses have been chosen as the most suitable vectors for this purpose, as they are neither pathogenic nor immunogenic for the patients and they can induce long-term expression of the transferred gene in the muscle cells. These therapeutic approaches have been developed in mouse models of LGMDs and are now being tested in affected humans, with promising results. However, one of the main barriers for these therapies seems to be the degenerative stage of the skeletal muscle of the patients to be treated, as these treatments are more effective in preventing muscle degeneration rather than reversing it. Therefore, early diagnosis of the diseases, when muscle degeneration is still not prominent, will be a key factor to achieve satisfactory outcomes from these gene transfer therapies.