Improved transduction of canine X-linked muscular dystrophy with rAAV9-microdystrophin via multipotent MSC pretreatment

Duchenne muscular dystrophy (DMD) is a severe congenital disease associated with mutation of the dystrophin gene. Supplementation of dystrophin using recombinant adeno-associated virus (rAAV) has promise as a treatment for DMD, although vector-related general toxicities, such as liver injury, neurotoxicity, and germline transmission, have been suggested in association with the systemic delivery of high doses of rAAV. Here, we treated normal or dystrophic dogs with rAAV9 transduction in conjunction with multipotent mesenchymal stromal cell (MSC) injection to investigate the therapeutic effects of an rAAV expressing microdystrophin (mDys) under conditions of immune modulation. Bone-marrow-derived MSCs, rAAVCMV-mDys, and a rAAV-CAG-luciferase (Luc) were injected into the jugular vein of a young dystrophic dog to induce systemic expression of mDys. One week after the first injection, the dog received a second intravenous injection of MSCs, and on the following day, rAAV was intravenously injected into the same dog. Systemic injection of rAAV9 with MSCs pretreatment improves gene transfer into normal and dystrophic dogs. Dystrophic phenotypes significantly improved in the rAAVmDys-injected dystrophic dog, suggesting that an improved rAAV-mDys treatment including immune modulation induces successful long-term transgene expression to improve dystrophic phenotypes.

Automated summary

The study showed that the combined treatment of rAAV and MSCs can effectively improve gene transfer in both normal and dystrophic dogs. Particularly under immune modulation conditions, rAAV expressing mDys treatment successfully induces long-term transgene expression, leading to improvement in dystrophic phenotypes.