Gene augmentation therapy restores vision and preserves photoreceptors in a mouse model of CNGA1-retinitis pigmentosa.

BACKGROUND: Retinitis pigmentosa (RP) is a leading cause of blindness affecting 2 million people worldwide. Mutations in cyclic nucleotide-gated channel alpha 1 (CNGA1) account for 2-8% of autosomal recessive RP with no available treatment. Here we further evaluate our previously developed Cnga1(-/-) mouse model. We aim to present detailed phenotype data and assess the therapeutic efficacy of gene augmentation in this model. METHODS: The retinal function and structure of Cnga1(-/-) mice were accessed from postnatal month 1 to 6. AAV8-hRHO-mCnga1 was constructed and delivered into the subretinal space of 2-week-old Cnga1(-/-) mice. Retinal function, photoreceptor survival, and vision-guided behavior were evaluated following treatment. RESULTS: Here we show that Cnga1(-/-) mice have a similar phenotype to human patients, characterized by an early loss of rod-mediated retinal function and progressive photoreceptor degeneration, which is nearly complete by 6 months of age. Gene augmentation therapy results in robust expression of correctly localized CNGA1 protein, sustained rescue of retinal function and long-term preservation of photoreceptors for at least 9 months. Treated mice also show improved performance in a vision-guided behavior test. RNA-seq reveals upregulation of genes associated with phototransduction. CONCLUSIONS: To the best of our knowledge, this work demonstrates for the first time that a gene augmentation approach can restore vision and preserves photoreceptors in an animal model of CNGA1-RP. These findings pave the way for future development of gene augmentation therapy for patients with CNGA1-RP.