Gene Therapy for Color Blindness

Abstract

Achromatopsia is a rare congenital cause of vision loss due to isolated cone photoreceptor dysfunction. The most common underlying genetic mutations are autosomal recessive changes in CNGA3, CNGB3, GNAT2, PDE6H, PDE6C, or ATF6. Animal models of Cnga3, Cngb3, and Gnat2 have been rescued using AAV gene therapy; showing partial restoration of cone electrophysiology and integration of this new photopic vision in reflexive and behavioral visual tests. Three gene therapy phase I/II trials are currently being conducted in human patients in the USA, the UK, and Germany. This review details the AAV gene therapy treatments of achromatopsia to date. We also present novel data showing rescue of a Cnga3^-/- mouse model using an rAAV.CBA.CNGA3 vector. We conclude by synthesizing the implications of this animal work for ongoing human trials, particularly, the challenge of restoring integrated cone retinofugal pathways in an adult visual system. The evidence to date suggests that gene therapy for achromatopsia will need to be applied early in childhood to be effective.

Keywords: Achromatopsia; Cone photoreceptors; Gene editing; Gene therapy.

Figure 1

(A) Representative photopic ERG traces recorded from CNGA3 (red) treated eye and untreated eye (black trace) of a TKO mouse. The response of an untreated wildtype control is also shown (grey trace). Scale bar is 50µV by 50 ms. (B) Immunohistochemical staining for CNGA3 in retinas of TKO mice following injection with rAAV2/5.CBA.CNGA3 but no labelling in an area of distant to the injection in the same eye (C). Scale bar 50µM.