UC Irvine

Visual function depends critically on the supply of visual chromophore, 11-cis-retinal, to the photoreceptor cells in the retina. Chromophore deficiency due to aging or mutations affecting its delivery and recycling in the eye by the retinal pigment epithelium (RPE) and the Müller cells cause a wide range of visual disorders. The cellular retinaldehyde-binding protein (CRALBP), expressed in both compartments, crucially aids in accelerating the recycling of visual chromophore. Here, we explored the potential of chromophore-loaded CRALBP in restoring vision in chromophore-deficient mice. We tested wild-type human CRALBP and its redox-sensitive A212C:T250C mutant, both pre-loaded with 9-cis-retinal, for their efficacy in delivering chromophore to the retina and restoring rod photoreceptor function in RPE65-deficient mice that cannot produce visual chromophore. We observed robust restoration of rod function both in the isolated retina treated with chromophore-loaded CRALBP and in vivo after a single intravitreal injection of wild-type or mutant CRALBP proteins. Notably, the recovery of rod visual function after exposure to bright light that photoactivated most of the visual pigment was greatly accelerated in CRALBP-treated RPE65-knockout mice compared to wild-type control mice. Together, our results highlight the therapeutic potential of CRALBP complexes in efficiently delivering visual chromophore to retinal rod photoreceptors.