Functional and Morphological Rescue of the Type I Ocular Albinism Murine Retina Following AAV-Mediated Gene Transfer.

X-linked recessive Type I Ocular Albinism (OA1) is a developmental disorder of the retina due to mutations in the OA1 gene expressed in the retinal pigment epithelium (RPE). The disease is characterized by foveal hypoplasia, misrouting of the optic fibers at the chiasm and RPE ultrastructural abnormalities. The Oa1 -/- mouse recapitulates many of the OA1 retinal morphological anomalies including a lower number of melanosomes of increased size in the RPE. To test the functionality of the Oa1 -/- retina we measured by electrophysiological methods its ability to dark adapt, which is impaired in forms of albinism other than OA1. Control C57/BL6 mice showed a characteristic kinetic of recovery of the bwave amplitude within 60 min following exposure to a pre-adapting saturating light. In contrast, the recovery of photoreceptor responses was significantly delayed in Oa1-/- mice. To test whether Adeno- Associated-Vector-(AAV) mediated Oa1 gene transfer was able to revert this functional abnormality and the characteristic melanosome landmarks of the Oa1 phenotype, two groups of animals at different ages were injected subretinally with a mixture of AAV2/1-CMVOa1+ AAV2/1-EGFP in the right eye and the same amount of AAV2/ 1-CMV-EGFP in the left eye. Dark adaptation in both eyes and groups was analyzed 1 month after gene transfer. The Oa1 -/- eyes that received only EGFP showed a delayed ability to dark adapt similar to the eyes of untreated Oa1 mutant mice. In the eyes that received the therapeutic vector the recovery was complete in 60 min: as in wild type animals. Electron microscopy analysis revealed a significant increase in the number of melanosomes in the RPE of the retina treated precociously with AAV. Our results suggest that post-natal Oa1 gene transfer in mice rescues some of the functional and morphological abnormalities that develop in the Oa1 -/- retina.