Nov. 3, 2008

Bodywide Gene Delivery Achieved With AAV9

Researchers at the University of Missouri, the University of North Carolina and Auburn University in Alabama have found that genes encased in a type 9 adeno-associated virus (AAV9) reached all the skeletal muscles of dogs after a single intravenous injection.

The finding is considered significant, because treating muscle disease with gene therapy is likely to require that the therapy reach all muscles after systemic administration.

MDA funded Dongsheng Duan at the University of Missouri, Joe Kornegay at the University of North Carolina and Bruce Smith at Auburn University for this work.

In a paper published online Sept. 30 in Molecular Therapy, Duan and colleagues describe experiments designed to determine the effectiveness of local and systemic injection of AAV9 as a potential gene therapy delivery method for muscle diseases such as Duchenne muscular dystrophy (DMD).

To test the AAV9 delivery system, they inserted a gene that carries instructions for the alkaline phosphatase protein into AAV9 shells. They first injected the gene-carrying shells directly into a muscle.

Genes injected directly into a muscle provoked an unwanted immune reaction if they were administered to mature animals. However, they were accepted well if given very early in life.

Researchers next tested whether bodywide gene delivery could be achieved by delivering gene-carrying AAV9 through a vein in four young dogs. Six months after the intravenous gene transfer, they found the alkaline phosphatase protein was produced in nearly every skeletal muscle. However, the intravenously administered genes failed to enter the heart muscle, which is affected in many muscle diseases.

"We're currently working to further improve the technique to achieve not only skeletal muscle but also heart muscle transduction [entry]," Duan said. "Many muscular dystrophy patients suffer from heart disease, so a technique that can reach both skeletal muscle and the heart will be more appealing.”

The investigators also note the importance of age at the time of gene delivery and suggest the immune response hurdle may be cleared in newborns, as their immature immune systems may not mount a vigorous response to therapy.