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.