Abstract
Purpose :
AAV-mediated gene therapy is an attractive option for the treatment of inherited retinal dystrophies. Retinitis Pigmentosa caused by mutations in PDE6B are potentially good candidates for such treatment, and different animal models are available for proof of concept and preclinical investigation. Among them, the rd10 mouse model, which displays a complete deficiency in PDE6B activity, exhibits rapid rod photoreceptor degeneration followed by secondary cone cell death. In this model we evaluated the biological activity of clinical-grade recombinant AAV2/5 vector batches encoding the human PDE6B cDNA (hPDE6B) under transcriptional control of a RK (Rhodopsin Kinase) promoter.
Methods :
rd10 mice were reared in dark environment until postnatal (PN) day 28. A volume of 1uL AAV vectors was injected subretinally at PN14 in a single eye. Two cohorts of 6 animals each were treated with two different vector doses: 1.6 x 10e9 and 5 x 10e9 vg/eye. The presence of a bleb after subretinal injection was controlled by OCT examination. At PN35, optical coherence tomographic examination (OCT) and electroretinogram (ERG) were performed. At PN60, OCT, ERG and quantitative optometric response (qOMR) were performed. Mice were sacrificed at PN65, and treated and control eyes were fixed and processed for morphological evaluation as well as immunohistochemistry (IHC).
Results :
In the high-dose group, a statistically significant improvement of retinal response to light stimulus (ERG and qOMR) was observed in the treated eye at the earliest time point of evaluation (PN35) and the correction was maintained until sacrifice. Retinal morphology evaluated by OCT was preserved and IHC revealed higher survival of photoreceptors in the treated eye compared to the contralateral eye. In the low-dose group, no statistically significant difference in ERG and qOMR was observed between treated and untreated eyes. However, significant preservation of photoreceptors in treated eyes was observed, mainly at the earliest time point and retinal morphology was partially preserved.
Conclusions :
AAV-mediated hPDE6B gene therapy is a valid strategy to prevent photoreceptor degeneration in a PDE6B-related RP model, which further supports the relevance of this approach in the clinic. Therapeutic threshold, however, appears as a critical parameter to achieve clinical benefit.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.