Gene therapy for muscular dystrophy

Gene therapy for muscular dystrophies requires that most, if not all, muscle fibers receive the appropriate gene to correct the underlying genetic defect. Nonspecific gene delivery into nonmuscle cells increases the chances of side effects that may or may not be revealed until these promiscuous vectors are used in humans. Furthermore, the use of large amounts of promiscuous vector increases the amounts of vector antigens and transgene product antigens that are delivered to immune cells, which may enhance T cell responses in humans that limit gene therapy.

Given these problems, the lab is developing approaches to physically target vectors to muscle while detargeting them from nontarget and immune cells. This project applies technologies developed in the laboratory for vector targeting and vector detargeting to improve the pharmacology of both adenovirus and adeno-associated virus vectors for muscle gene therapy.

Additional challenges in gene therapy focus on the huge size of genes that are damaged in muscular dystrophies. One example is Miyoshi myopathy (MM), which is caused by mutations in the dysferlin gene. MM is transmitted as an autosomal recessive genetic disease and poses a unique challenge to current gene therapy approaches given that its genomic copy exceeds the capacity of all current vectors. In contrast, its complementary DNA (cDNA) is 6,243 base pairs, putting it in the range of some larger gene therapy vectors. This challenges adeno-associated virus (AAV) vectors, currently the most popular gene therapy vector, which can at most package 4.5 kilobase pairs.

Other groups are developing approaches to enable AAV to express dysferlin. Given this, the team is testing if large capacity adenovirus vectors can carry this large gene and evade the immune system.