Long-term preservation of photoreceptor function and structure following early-stage treatment by AAV-mediated gene augmentation in canine model of NPHP5 Leber congenital amaurosis

Abstract

Purpose : A C-terminal truncation of NPHP5 (IQCB1) causes a photoreceptor ciliopathy with an early onset, rapidly progressive retinal degeneration in dogs. By 6 wks of age, rod responses are markedly reduced in amplitude or absent, and cone responses are not recordable. The absence of cone function correlates with the lack of cone outer segments even though there is preservation of cone inner segments which offers the possibility for successful gene therapy. We now report on long-term efficacy of early-stage treatment.

Methods : Subretinal injections of 70 µl of cNPHP5 therapeutic vectors, AAV2/5-hIRBP- or scAAV2/8 (Y733F)-hGRK1-, at titers ranging from 1.5 – 5 E11 or E12 vg/ml were made into one eye of affected dogs at 5-6 wks of age, with fellow eyes serving as untreated controls. Photoreceptor structure and function were quantified by sdOCT and full-field ERGs. Visual behavior was assessed after ~ 1 yr following treatment using an obstacle avoidance course to separately test the treated and contralateral control eyes.

Results : Gene therapy restored cone function and improved rod function within 6-7 wks after treatment, and there were no treatment related complications. Post treatment functional evaluation showed sustained preservation of ERG rod and cone function for time periods ranging from 1.4 to 2.7 yrs after therapy. Testing in an obstacle avoidance course under scotopic and photopic illumination showed retained functional vision in the treated eyes under all illumination conditions. Treatment blebs were associated with significantly retained photoreceptor layer which was robust with better ONL preservation at the higher vector concentrations.

Conclusions : In spite of the very severe and rapidly progressive photoreceptor degeneration in NPHP5-LCA affected dogs, AAV-mediated gene augmentation restores rod and cone function, preserves vision and photoreceptor structure for time periods greater than 1.4-2.7 years without any deleterious effects. As the extent of photoreceptor disease is quite severe and advanced at the time of early-stage treatment, the results augur well for future translational applications.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.