AAV2-mediated ocular gene therapy for infantile neuronal ceroid lipofuscinosis.

Infantile neuronal ceroid lipofuscinosis (INCL) is a neurodegenerative disorder caused by mutations in the gene encoding the lysosomal enzyme palmitoyl protein thioesterase-1 (PPT1). The earliest clinical sign in INCL is blindness, followed by seizures, cognitive deficits, and early death. Little is known about the progression of the visual deficits in INCL. Here we characterize the progressive retinal dysfunction and examine the efficacy of AAV2-mediated ocular gene therapy in the murine model of INCL. Significant decreases in both mixed rod/cone and pure cone electroretinographic amplitudes were observed at as early as 2 months of age. Intravitreal injection of AAV2-PPT1 increased enzyme levels in the eye to greater than normal levels. The increased PPT1 activity correlated with improvements in the histological abnormalities as well as both mixed rod/cone and pure cone functions. We also demonstrated that palmitoyl protein thioesterase-1 activity was detected in the brain following intravitreal injection. The brain activity is likely due to anterograde axonal transport along the optic tracts. Interestingly, the degree of neurodegeneration throughout the visual pathways of the brain was greatly reduced in AAV-treated INCL mice. Therefore, intravitreal AAV-mediated gene therapy has direct benefits to the eye and to distal sites in the brain along the visual pathways.