904. The Systemic Human Immune Response to Intraparenchymal Administration of AAV

BACKGROUND Recombinant AAV-ASPA has been developed for gene delivery to the CNS for Canavan Disease, a rare leukodystrophy with no treatment. This NINDS funded project is the first clinical study of a viral vector used for gene delivery in a neurodegenerative disorder. METHODS Subjects were administered AAV serotype 2 at a maximum dose of 1 × 10E12 vector genomes per subject, via intraparenchymal infusions to the subcortex . The immune response and safety profiles were monitored in the follow-up of 13 subjects who ranged from 3-82 months of age at the time of vector administration. RESULTS Following rAAV2 administration, we found no evidence of AAV2 neutralizing antibody titers in serum for the majority of subjects tested. In a subset of subjects low to moderately high levels of AAV2 neutralizing antibody with respect to baseline were detected. In all subjects, there were minimal systemic signs of inflammation or immune stimulation. In subjects with catheter access to the brain lateral ventricle, cerebrospinal fluid was examined and there was a complete absence of neutralizing antibody titers with no overt signs of brain inflammation. CONCLUSIONS rAAV2 vector administration to the human CNS appears well tolerated. The low levels of immune response to AAV2 detected in this study suggest at this dose and with intraparenchymal administration this approach is relatively safe. Long-term monitoring of subjects and expansion to Phase II/III will be necessary in order to make definitive statements on safety and efficacy.