Intramuscular administration of recombinant adeno-associated virus 2 alpha-1 antitrypsin (rAAV-SERPINA1) vectors in a nonhuman primate model: safety and immunologic aspects.

We performed a series of studies in baboons to evaluate the safety of intramuscular administration of rAAV vector expressing the alpha-1 antitrypsin (AAT) gene (SERPINA1) in a nonhuman primate model. Initial experiments performed with an rAAV vector expressing the human SERPINA1 gene (at doses of up to 5 x 10(12) vector genomes/kg) resulted in the generation of anti-human AAT antibodies, which correlated with a loss of detectable transgene expression. Subsequent studies made use of the baboon SERPINA1 gene tagged with a short (10-amino-acid) c-myc tag. When animals were sacrificed, 4 months after vector injection, transduced myofibers showed efficient transgene expression without detectable humoral immune responses. Mild inflammation was observed in and near the sites of injection in some vector- and saline-injected animals, but serum creatine kinase (CK) values were normal in nearly every case. Real-time PCR was also performed 4 months after injection on gonadal tissue to evaluate the risk of germline transmission. No vector sequences were detected in the gonadal tissues from these animals. These studies indicate that the risks of immune reaction and germline transmission after intramuscular injection of rAAV-SERPINA1 in nonhuman primates are relatively low within the range of vector doses studied.