Immediate and long-term safety of recombinant adeno-associated virus injection into the nonhuman primate muscle

Previous studies on distribution and toxicity of viral vectors administered in monkeys indicated that the nonhuman primate model has a reasonable pred ictive value for clinical applications. In this study, eight macaques were injected intramuscularly with recombinant adeno-associated virus (rAAV) at doses similar to those administered to hemophilia B patients, and followed to analyze the dissemination and shedding in biological samples and long-te rm persistence in distant organs. Following rAAV delivery, we found vector genome in various biological fluids for up to 6 days and infectious particl es exclusively in the serum during the first 48-72 hours. rAAV sequences we re detected in peripheral blood mononuclear cells (PBMC) for up to 10 month s. At necropsy, 8 to 18 months after rAAV delivery, rAAV sequences were fou nd in lymph nodes and livers but never in the gonads. Tissue examination, o f liver in particular, showed no abnormalities. We concluded that during ou r experimental time frame, rAAV-mediated gene transfer into skeletal muscle of macaques seemed to be safe with respect to the recipient and the enviro nment. However, it was associated with a transient viremia and the persiste nce of rAAV sequences in PBMC, lymph nodes, and liver, the long-term conseq uences of which remain unknown.