Abstract
Complete congenital achromatopsia is a devastating hereditary visual disorder. Mutations in the CNGB3 gene account for more than 50% of all known cases of achromatopsia. This work investigated the efficiency of subretinal (SR) delivered AAV8 (Y447, 733F) vector containing a human PR2.1 promoter and a human CNGB3 cDNA in Cngb3 -/-/ Nrl -/- mice. The Cngb3 -/-/ Nrl -/- mouse was a cone-dominant model with Cngb3 channel deficiency, which partially mimicked the all-cone foveal structure of human achromatopsia with CNGB3 mutations. Following SR delivery of the vector, AAV-mediated CNGB3 expression restored cone function which was assessed by the restoration of the cone-mediated electroretinogram (ERG) and immunohistochemistry. This therapeutic rescue resulted in long-term improvement of retinal function with the restoration of cone ERG amplitude. This study demonstrated an AAV-mediated gene therapy in a cone-dominant mouse model using a human gene construct and provided the potential to be utilized in clinical trials.
Highlights
In the human retina, photoreceptor cyclic nucleotide-gated (CNG) channels play a pivotal role in phototransduction
The cone photoreceptor CNG channel is composed of A3 and B3 subunits, whereas the rod photoreceptor CNG channel is formed by A1 and B1 subunits[4,5,6,15]
CNGB3 shares a common topology with CNGA3 and possesses a poreforming region, the B3 subunit does not form a functional channel without A3 subunits[14,34]
Summary
Photoreceptor cyclic nucleotide-gated (CNG) channels play a pivotal role in phototransduction. Phototransduction relies on the function of CNG channels in both rod and cone photoreceptor outer segment plasma membranes[1,2]. CNG channels comprise two structurally related A and B subunits: the rod photoreceptor CNG channel is composed of CNGA1 and CNGB1. Subunits, whereas the cone photoreceptor is composed of CNGA3 and CNGB3 subunits[2,3,4,5,6]. Recent studies have shown that mutations in CNGA3 or CNGB3 cause clinically indistinguishable forms of congenital achromatopsia (ACHM)[7]. ACHM or rod monochromatism is an autosomal recessive hereditary visual disorder characterized by the absence of functional cone photoreceptors in infancy, affecting one in approximately 30 000 individuals worldwide[7].
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