510. Neonatal Gene Transfer with Non-Human Primate AAV Vector Serotypes Results in Widespread Transduction and Gene Activity in the Mouse Brain

Abstract

Mucopolysaccharidosis (MPS) VII is a heritable lysosomal storage disease caused by the deficiency of Beta-glucuronidase (GUSB). MPS VII is a chronic and progressive multiorgan disorder with signs of pathology presenting early in life. Most therapeutic approaches for MPS VII have focused on adult treatments. Although these approaches can reverse storage lesions, the central nervous system (CNS) is more difficult to treat. Our lab has previously shown complementary patterns of transduction between AAV1 and after neonatal injection into the lateral cerebral ventricles (Passini et al., 2003; Journal of Virology). Using an AAV2 ITR backbone, we investigated neonatal gene transfer to the CNS of normal and MPS VII mice with capsid proteins from AAV7, AAV8, and AAV9. We injected 1.8 |[times]| 10^10 genomes of vector into the lateral cerebral ventricles (2 |[mu]|l each) of normal and MPS VII mice at birth (P O.5). At one month postinjection, each of the AAV serotypes demonstrated extensive and widespread GUSB activity and mRNA expression in the brain, but variations in transduction patterns related to substructures of the brain were observed. AAV 2/7 and AAV 2/8 transduced more cells and expressed more GUSB compared to AAV 2/9. Significant amounts of GUSB were present in the ganglion cells of the retina and spinal cord for each of the tested AAV serotypes. Evaluations of AAV gene transduction patterns and lysosomal storage correction for the eye, brain and spinal cord are ongoing. These results suggest that AAV7, AAV8, and AAV9 are suitable vectors for targeting the CNS, and may be useful for CNS gene therapy.