Abstract
Purpose :
We have previously demonstrated that arrestin1 can be modified to disinhibit enolase1, thus increasing the rate of glycolysis in photoreceptors. In published studies, we showed that AAV delivery of this modified arrestin1 (known as ArrGG) slows the rate of degeneration in the P23H-rhodopsin model of retinitis pigmentosa. In this study, we apply the ArrGG to two additional models of inherited retinal disease to demonstrate that the slowing of retinal degeneration from the modified arrestin1 is not specific to rhodopsin-based genetic defects, but instead can be applied to a broader range of degenerations originating from other defects in other genes.
Methods :
ArrGG packaged in a capsid variant of AAV2 (Y272F, Y444F, Y500F, Y730F, and T491V) was delivered intravitreally to rd6 (Mfrprd6/rd6) and rd10 (Pde6brd10/rd10) in one eye at P30. Control animals received an injection of buffered saline solution. OCT was performed at 30-day intervals to monitor longitudinal morphological preservation of the retina. Histological examination of frozen sections was performed post-mortem.
Results :
Mice with a defect in the Pde6b gene (rd10), which degenerate rapidly, were treated in one eye at P30 with AAV-ArrGG or with buffered-saline solution. Eyes receiving ArrGG retained 64% more outer nuclear layer (ONL) thickness at 30 days post-injection compared to untreated or buffer-treated controls (ArrGG: 17.1+/-0.9 µm; Control: 11.5+/-0.5 µm; p<0.001). Mice with a defect in the MFRP gene (rd6), which degenerate more slowly than the rd10 mice, were similarly treated with AAV-ArrGG or BSS. Eyes receiving ArrGG retained 14.5% more ONL thickness at 30 post-injection compared to untreated or buffer-treated controls (ArrGG: 49.9+/-1.65 µm; Control: 43.6+/-0.1 µm; p<0.014). This differential was maintained out to at least 90 days and is continuing to be assessed.
Conclusions :
The successful slowing of retinal degeneration in three models of inherited retinal degeneration (rhodopsin, PDE, and MFRP) using ArrGG offers promising results, suggesting that upregulation of glycolysis using this modified arrestin1 may have broad application for slowing retinal degeneration in a gene-agnostic approach.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.