Long-term follow up of gene therapy for NPHP5-LCA in a canine model shows restoration of photoreceptor function and vision for > 5 years

Abstract

Purpose : NPHP5 gene augmentation successfully rescues photoreceptor structure, function, and vision for up to 6 months when delivered at early-stage disease in the canine NPHP5 model of LCA, a severe form of inherited childhood blindness (Aguirre et al. Mol Ther 2021). We now report on the long-term (up to 5.4 years) follow-up of 20 mutant dogs treated unilaterally at more advanced stages of disease including: early/mid (n=3), mid (n=4), late (n=9) and very late (n=4) stages.

Methods : Dogs were subretinally-injected (0.1-0.15 mL) with a scAAV2/5 or scAAV2/8_(C&G+T494V) vector construct (4.74 x10¹² vg/mL) carrying full-length canine or human NPHP5 cDNA under control of a GRK1 promoter. Throughout the course of the study, photoreceptor structure and function were assessed by SD-OCT and ERG. Rod- and cone-mediated visual behavior was evaluated in an obstacle avoidance course under scotopic and photopic illumination.

Results : While progressive ONL thinning was seen by OCT over time, ONL rescue was still detectable in the treated retinal area at the latest post injection (PI) time-point (up to ~ 5 years in early/mid, and mid stage groups; and up to ~ 3 years in the late-stage group). No ONL preservation was seen in untreated areas of injected eyes, nor in BSS or uninjected contralateral eyes beyond the visual streak. ERG showed restoration of both rod- and cone-mediated function in all AAV-NPHP5 injected eyes, with the exception of dogs from the very late-stage group in which only cone-mediated ERG was restored. Vision testing performed in a subset (n=13) of dogs showed persistent recovery in the early/mid- (3 out of 3), mid- (2 out of 2), late- (4 out of 4), and very late- (1 out of 2) stage groups. Vision restoration was independently documented in the single dog from the very late-stage group that refused to enter the obstacle course by using a modification of the protocol.

Conclusions : These results show long-term (3 - 5.4 years) restoration of photoreceptor function and preservation of structure as well as visually-guided behavior following subretinal NPHP5 gene augmentation therapy delivered at patient-relevant advanced stages of disease. A treatment effect was detectable by ERG as early as 4-8 weeks PI. In addition, these results show that cones are receptive to very late-stage intervention even when most rod photoreceptors are lost.

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