Muscular dystrophy gene therapy in small animal models

Abstract

Muscular dystrophies are inherited neuromuscular disorders characterized by progressive muscle loss and weakness. The morbidity and fatality associated with the diseases and a lack of effective treatment have prompted urgent search for novel therapeutics. Gene therapy is one of the frontiers. Currently, adeno-associated viral (AAV) vector-mediated gene transfer offers a powerful tool for muscular dystrophy gene therapy for both skeletal as well as cardiac muscles, by means of local, regional, and systemic deliveries. However, AAV has a packaging limit smaller than 5,000 nucleotides. Larger genes such as dystrophin will need to be truncated to functional miniature versions to be packaged in AAV particles. In this chapter, we will illustrate how gene therapy with AAV vectors is applied to small rodent muscular dystrophy models including those that mimic Duchenne muscular dystrophy (the dystrophin-deficient mdx mice), congenital muscular dystrophy (the laminin α2 knockout dy/dy mice), and limb-girdle muscular dystrophy (the delta-sarcoglycan deficient TO-2 hamsters). Challenges in larger animal studies and prospects for clinical trials in muscular dystrophies will be briefly discussed.