making muscle wasting history

Adeno-associated virus (AAV) vector is a potential tool of gene therapy for treatment of genetic neuromuscular disorders. It is a non-pathogenic and replication-defective viral vector without any viral open reading frame that is able to infect effectively non-dividing cells, such as those of skeletal muscle and the central nervous system. It is widely believed that AAV vectors offer long-term expression of the transferred gene without immune response against the transferred gene product, and it has been demonstrated that intramuscular injection of AAV vectors expressing immunogenic proteins does not stimulate humoral and cellular immune response to transgene products in immunocompetent mice. Thus, AAV vectors may be applicable to treatment of inherited neuromuscular disorders such as DMD.

In fact, the AAV vector has been successfully introduced into -sarcoglycan-deficient hamsters and -sarcoglycan-deficient mice, animal models of limb girdle muscular dystrophies (LGMD). A recent report, however, showed lower levels of transgene expression together with substantial immune response to the therapeutic transgene product in -sarcoglycan-null mice. Restriction of transgene expression to the muscle is important to avoid transgene expression in antigen-presenting cells (APCs).

Although AAV vector-mediated gene transfer is an attractive option for treatment of DMD, the size of the foreign gene is limited to 4.7-4.9 kb of exogenous DNA. Therefore, full-length dystrophin (14 kb) and mini-dystrophin (6.4 kb) cDNAs are too large to be incorporated into AAV vector as the therapeutic gene. It was previously reported that rod-truncated micro-dystrophin, which is encoded by 3.7 kb cDNA, could effectively accumulate at the sarcolemma and recover dystrophin-associated proteins after adenovirus-mediated gene transfer into mdx skeletal muscles. Wang et al reported the effective transfer of two kinds of micro-dystrophin cDNAs (<4.2 kb) into mdx skeletal muscle using AAV vectors. The AAV vector treatment ameliorated dystrophic pathology in mdx muscle, demonstrating micro-dystrophin cDNA to be a good candidate for insertion into the AAV vector.
In conclusion, this research suggest the importance of transient immunosuppression before the transgene product accumulates in the affected muscle.