Efficacy of Gene Therapy Is Dependent on Disease Progression in Dystrophic Mice with Mutations in the FKRP Gene

• Main Authors: Charles Harvey Vannoy, Will Xiao, Peijuan Lu, Xiao Xiao, Qi Long Lu
• Format: Article
• Language: English
• Published: Elsevier 2017-06-01
• Series: Molecular Therapy: Methods & Clinical Development
• Subjects: adeno-associated virus; dystroglycanopathy; fukutin-related protein; gene therapy; muscular dystrophy
• Online Access: http://www.sciencedirect.com/science/article/pii/S2329050117300426

Loss-of-function mutations in the Fukutin-related protein (FKRP) gene cause limb-girdle muscular dystrophy type 2I (LGMD2I) and other forms of congenital muscular dystrophy-dystroglycanopathy that are associated with glycosylation defects in the α-dystroglycan (α-DG) protein. Systemic administration of a single dose of recombinant adeno-associated virus serotype 9 (AAV9) vector expressing human FKRP to a mouse model of LGMD2I at various stages of disease progression was evaluated. The results demonstrate rescue of functional glycosylation of α-DG and muscle function, along with improvements in muscle structure at all disease stages versus age-matched untreated cohorts. Nevertheless, mice treated in the latter stages of disease progression revealed a decrease in beneficial effects of the treatment. The results provide a proof of concept for future clinical trials in patients with FKRP-related muscular dystrophy and demonstrate that AAV-mediated gene therapy can potentially benefit patients at all stages of disease progression, but earlier intervention would be highly preferred.