Safety and long-term efficacy of AAV2-BEST1 gene augmentation therapy in canine model of Best vitelliform macular dystrophies

Abstract

Purpose : Canine bestrophinopathy (cBest) is a translational model of human BEST1-associated maculopathies that recapitulates the full spectrum of clinical and molecular disease aspects observed in patients. We have previously shown proof-of-concept for AAV2-mediated BEST1 gene augmentation therapy in cBest, and demonstrated reversal of gross vitelliform lesions as well as correction of light-modulated microdetachment after a single subretinal injection. The aim of this study was to assess the long-term efficacy of canine and human BEST1 transgene expression in cBest eyes followed up to 80 months post treatment.

Methods : cBest dogs (n=12) injected unilaterally with AAV2 expressing either canine or human BEST1 (0.5 - 5.0E+11 vg/mL) were monitored clinically and imaged serially using cSLO/SD-OCT. cBest phenotype rescue was assessed in vivo based on topographic maps of ONL thickness and quantification of IS/OS-RPE/T distance, and ex vivo by immunohistochemistry and confocal microscopy in comparison to AAV-untreated contralateral control eyes.

Results : All cBest dogs showed good ophthalmological tolerance to the AAV2/2-hVMD2-BEST1 vector and long-term persistence of AAV-mediated BEST1 transgene expression, with no adverse effects or off-target distribution up to 80 months post injection. En face and cross-sectional imaging revealed reversal of macro- and microdetachments with either canine or human BEST1 transgenes. Quantitative measurements confirmed complete amelioration of light-mediated microdetachments, with the IS/OS-RPE/T distance returning to normal levels in treated regions. Ex vivo assessments of the retina demonstrated clear structural rescue at vector-treated bleb areas with restoration of cytoarchitecture at the RPE-photoreceptor interface. In contrast, the disease in AAV-untreated control eyes progressed to more advanced stages, reaching the end-stage atrophic lesions in oldest dogs.

Conclusions : We report long-term safety and efficacy of AAV2-mediated BEST1 gene augmentation therapy evidenced in 3 different canine BEST1 genotypes. The results showing sustained reversal of macular and extramacular lesions as well as amelioration of hypersensitivity to light hold promise for safety and efficacy in future human clinical trials of BEST1-associated maculopathies.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.