Rhesus macaque model of Bardet-Biedl syndrome: Progression and response to gene therapy

Abstract

Purpose : Animal models are urgently needed that closely replicate human inherited retinal degenerations, particularly those affecting the macula. We identified a rhesus macaque model of Bardet-Biedl syndrome (BBS) due to a BBS7 mutation that shows cardinal features of the disease in humans, including rapid retinal degeneration beginning in the macula, renal dysfunction, obesity and brain abnormalities. This study characterized progression of retinal degeneration over the first 2.5 years and the effects of gene therapy with a novel AAV capsid able to transduce a wide area of the primate retina.

Methods : Embryos were generated in vitro using ova and sperm from BBS7 carriers, and BBS7^-/- embryos were transferred to surrogate dams. Three resulting BBS7^-/- infants were assessed by multimodal retinal imaging and ERG. One was followed to 2.5 years of age, and at 2 years received uniocular subretinal gene therapy with AAV.SPR-GRK1-BBS7 in 3 blebs surrounding the fovea. An unaffected monkey was co-injected with AAV.SPR-GRK1-BBS7 and AAV.SPR-GRK1-GFP to assess spread of retinal transduction.

Results : OCT imaging from 4 weeks of age showed severe attenuation of the EZ line, consistent with absence or abnormal structure of photoreceptor outer segments. Thickness of the macular outer nuclear layer was 80% of normal at 4 months, declining to 10-20% by 2 years. Full-field photopic and scotopic ERGs had delayed response kinetics; amplitudes were substantially reduced at 4 months and declined progressively with age. The multifocal ERG showed severe, progressive loss of central cone function, with nearly extinguished responses in the central 30° by 6 months. Gene therapy at 2 years resulted in the slowing of degeneration in the macula, while the untreated retina showed continued thinning. In a normal eye receiving the AAV.SPR vectors for both BBS7 and GFP, strong GFP fluorescence was seen across the entire retina.

Conclusions : The rhesus macaque model of BBS is the first NHP model of retinitis pigmentosa with a known genetic cause, and its phenotype closely mirrors key features of the human condition. The retinal degeneration phenotype was confirmed in the early months in three infants, adding to information from older animals previously identified at 3.5 - 6 years. Furthermore, initial results of gene therapy with the laterally spreading AAV.SPR vector showed slowing of degeneration, even at an advanced stage of the disease.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.