Background: Leber congenital amaurosis (LCA), a heterogeneous early-onset retinal dystrophy, accounts for ∼15% of inherited congenital blindness. One cause of LCA is loss of the enzyme lecithin:retinol acyl transferase (LRAT), which is required for regeneration of the visual photopigment in the retina. Methods and Findings: An animal model of LCA, the Lrat-/- mouse, recapitulates clinical features of the human disease. Here, we report that two interventions-intraocular gene therapy and oral pharmacologic treatment with novel retinoid compounds-each restore retinal function to Lrat-/- mice. Gene therapy using intraocular injection of recombinant adeno-associated virus carrying the Lrat gene successfully restored electroretinographic responses to ∼50% of wild-type levels (p < 0.05 versus wild-type and knockout controls), and pupillary light responses (PLRs) of Lrat-/- mice increased ∼2.5 log units (p < 0.05). Pharmacological intervention with orally administered pro-drugs 9-cis-retinyl acetate and 9-cis-retinyl succinate (which chemically bypass the LRAT-catalyzed step in chromophore regeneration) also caused long-lasting restoration of retinal function in LRAT-deficient mice and increased ERG response from ∼5% of wild-type levels in Lrat-/- mice to ∼50% of wild-type levels in treated Lrat -/- mice (p < 0.05 versus wild-type and knockout controls). The interventions produced markedly increased levels of visual pigment from undetectable levels to 600 pmoles per eye in retinoid treated mice, and ∼1,000-fold improvements in PLR and electroretinogram sensitivity. The techniques were complementary when combined. Conclusion: Intraocular gene therapy and pharmacologic bypass provide highly effective and complementary means for restoring retinal function in this animal model of human hereditary blindness. These complementary methods offer hope of developing treatment to restore vision in humans with certain forms of hereditary congenital blindness.
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