Limb-girdle muscular dystrophies (LGMDs) represent a major group of muscle disorders. Treatment is sorely needed and currently expanding based on safety and efficacy adopting principles of single-dosing gene therapy for monogenic autosomal recessive disorders. Gene therapy has made in-roads for LGMD and this review describes progress that has been achieved for these conditions. This review first provides a background on the definition and classification of LGMDs. The major effort focuses on progress in LGMD gene therapy, from experimental studies to clinical trials. The disorders discussed include the LGMDs where the most work has been done including calpainopathies (LGMD2A/R1), dysferlinopathies (LGMD2B/R2) and sarcoglycanopathies (LGMD2C/R5, LGMD2D/R3, LGMD2E/R4). Early success in clinical trials provides a template to move the field forward and potentially apply emerging technology like CRISPR/Cas9 that may enhance the scope and efficacy of gene therapy applied to patient care.
Keywords: AAV; gene therapy; limb-girdle muscular dystrophy.
Lay abstract Limb-girdle muscular dystrophy is a term that is applied to a group of relatively rare forms of muscular dystrophy. The term ‘LGMD’ was introduced in the 1950’s, but there were no strict rules for defining the condition. This changed as a result of the 229th European Neuromuscular Center International Workshop in 2017 providing a clear definition and classification discussed in this article. Limb-girdle muscular dystrophy is now recognized as a genetic muscle disease with an elevated serum creatine kinase and dystrophic changes on muscle histology. Most treatments up to now rely on supportive measures for heart and lungs and assisting the physical limitations. Medications have not proven to be beneficial to stop progression of disease. This article focuses on new innovations of treatment that target the effected gene and the use special methods to replace the abnormal gene.