AAV-mediated Gene Therapy Halts Retinal Degeneration in PDE6β-deficient Dogs

Abstract

We previously reported that subretinal injection of AAV2/5 RK.cpde6β allowed long-term preservation of photoreceptor function and vision in the rod-cone dysplasia type 1 (rcd1) dog, a large animal model of naturally occurring PDE6β deficiency. The present study builds on these earlier findings to provide a detailed assessment of the long-term effects of gene therapy on the spatiotemporal pattern of retinal degeneration in rcd1 dogs treated at 20 days of age. We analyzed the density distribution of the retinal layers and of particular photoreceptor cells in 3.5-year-old treated and untreated rcd1 dogs. Whereas no rods were observed outside the bleb or in untreated eyes, gene transfer halted rod degeneration in all vector-exposed regions. Moreover, while gene therapy resulted in the preservation of cones, glial cells and both the inner nuclear and ganglion cell layers, no cells remained in vector-unexposed retinas, except in the visual streak. Finally, the retinal structure of treated 3.5-year-old rcd1 dogs was identical to that of unaffected 4-month-old rcd1 dogs, indicating near complete preservation. Our findings indicate that gene therapy arrests the degenerative process even if intervention is initiated after the onset of photoreceptor degeneration, and point to significant potential of this therapeutic approach in future clinical trials.

Transplantation of Human Embryonic Stem Cell-Derived Retinal Tissue in the Subretinal Space of the Cat Eye

“…There are issues with and limitations to both approaches [13,15,22,[25][26][27][28][29][30][31]. However, there is a clear similarity between grafted retinal sheets and some successful gene augmentation therapies of RP and Leber congenital amaurosis models, where the treated retinal areas remain as surviving patches of retina [32], which maintain visual function [33][34][35][36]. Similar to patches of retina preserved by gene augmentation therapy, the islands of transplanted mutation-free retina have the potential to survive, and with synaptic connectivity to the host, at least partially restore visual function [15,16,18,19,[37][38][39][40].…”

Novel PDE6B Mutation Presenting with Retinitis Pigmentosa – A Case Series of Three Patients

“…Recent advances now allow causal treatment of the underlying gene defect in the eye for RP caused by specific mutations [4 -7]. In PDE6Β mutations, a gene treatment has been successful in a dog model [25,26]. For human patients with RP related to a PDE6Β mutation, a phase I/II study is currently ongoing (https://clinicaltrials.…”

Large Animal Models of Inherited Retinal Degenerations: A Review

“…Therefore, it appears that the alpha subunit is necessary for the beta subunit to be maintained, while the beta subunit is not essential for the maintenance of the alpha subunit. Adeno-associated gene therapy has been shown to halt retinal degeneration in the rcd1 dog [50].…”