Inactivation of cellular retinol-binding protein 1 protects against bis-retinoid accumulation and light-induced retinal degeneration in mice.

Delayed clearance of all-trans-retinal (at-RAL) in photoreceptors is linked to prevalent retinal diseases such as Stargardt disease, rod-cone dystrophies, and age-related macular degeneration. Pharmacological modulation of retinoid metabolism in the eye presents a promising therapeutic strategy, with cellular retinol-binding protein 1 (RBP1) emerging as a potential target. However, it lacks genetic validation as a therapeutic target in an animal model of human disease. Thus, we investigated the effect of the Rbp1 gene inactivation on the phenotype of the Abca4-/-/Rdh8-/- model of Stargardt disease. Triple knockout (Abca4-/-/Rdh8-/-/Rbp1-/-) mice were protected against light-induced retinal degeneration. RBP1 deficiency also slowed bis-retinoid accumulation in aged animals. Furthermore, pharmacological inhibition of RBP1 alleviated the retinal degeneration phenotype. These findings provide both genetic and pharmacological evidence supporting RBP1 as a promising therapeutic target for retinal degenerative diseases associated with impaired all-trans-retinal clearance.