Gene therapy rescues photoreceptor function, morphology and survival in a pre-clinical model of CDHR1-associated retinal degeneration

Abstract

Purpose : To evaluate the efficacy and safety of retinal gene therapy in a pre-clinical model of CDHR1-associated retinal degeneration – an as yet untreatable, blinding disorder characterised by progressive cone and rod photoreceptor degeneration.

Methods : Cdhr1^-/-(n=28) and C57BL/6J control mice (n=23) underwent paired sub-retinal injections of AAV8.GRK1.CDHR1 (1.5x10⁸) and PBS vehicle control in the fellow eye at 4 weeks of age. Dark- and light-adapted electroretinography (ERG) was undertaken to 8 months post-injection. Photoreceptor layer thickness and outer retinal morphology were compared using optical coherence tomography (OCT) imaging to 6 months post-injection.

Results : In Cdhr1^-/- mice, sub-retinal AAV8.GRK1.CDHR1 rescued A-wave amplitudes (p<0.0001 at all time points) and B-wave amplitudes (p<0.0001 from 6 months) on dark-adapted ERG versus PBS-injected control eyes (Fig.1). Light-adapted flicker ERG amplitudes were greater in AAV-treated eyes at 8-months post-injection (p<0.0001).

AAV8.GRK1.CDHR1 preserved photoreceptor layer thickness in the superior retina versus PBS-injected eyes at 6-months post-injection (mean: 76.6μm versus 49.7μm; p<0.0001; Fig.2). OCT changes consistent with the regeneration of photoreceptor outer segments and restoration of ellipsoid zone reflectivity were only identified in AAV-treated eyes (p<0.0001; Fig.2).

In C57BL/6J mice, there was no difference in ERG assessments (A-wave, p=0.65; B-wave, p=0.47; Cone responses, p=0.09; Fig.1) or photoreceptor thickness measurements at 6 months between AAV and PBS-injected eyes (p=0.19; Fig.2).

Conclusions : These data provide proof-of-principle of the efficacy and safety of CDHR1 gene therapy in a pre-clinical model of CDHR1-associated retinal degeneration. Rod and cone rescue occur through prevention of photoreceptor cell death and photoreceptor outer segments may regenerate. A follow-on clinical trial in patients with CDHR1-associated retinal degeneration is warranted.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.

 

Fig 1. Functional data. CDHR1 gene therapy rescues rod and cone photoreceptor function in Cdhr1^-/- mice on dark- and light-adapted electroretinography. Toxic effects are not detected in C57BL/6J mice.

 

Fig 2. Structural data. CDHR1 gene therapy slows photoreceptor cell death (A) and regenerates photoreceptor outer segments (C&D) in Cdhr1^-/- mice to 6-months post-injection. Retinal thinning is not observed in C57BL/6J mice (B).