Abstract
Purpose :
To investigate the efficacy of retinoschisin (Rs1) gene rescue in a mouse model (Rs1-KO) of juvenile X-linked retinoschisis (JXLR) through administration of low dose AAV2/4 – RS1 with an Ef1α promoter.
Methods :
An AAV2/4-RS1-Ef1α promoter vector was delivered by subretinal 2 ul injections of 2E9/ml in Rs1-KO mice (N=7). Injections occurred on postnatal days 18-26. Full field Electroretinogram (ERG), Optical coherence tomography (OCT), and a visually guided swim assay (VGSA), were chosen as endpoints to assess efficacy. ERGs were completed at one, two-, and five-months post injection (PI). OCTs were completed at 3 weeks, 2 months, and 4 months PI using a masked retinoschisis severity score. Mice underwent a VGSA performed in light and dark conditions to assess functional vision at six months of age. Experimental eyes were compared to untreated fellow eyes as well as eyes of untreated Rs1-KO mice (N=13).
Results :
ERG: At one-month PI, treated eyes showed significantly higher b-wave amplitudes (p=0.0187) than untreated eyes on light adapted 3.0 cone ERG, which persisted until 5 months PI (p=0.0029). For the 5 Hz flicker, a pure cone response, treated eyes showed higher amplitude at one and two months than untreated eyes (p=0.0014 and p=0.0002), but lost significance by 5 months PI. Dark adapted rod amplitudes were not significantly different between treated and untreated eyes at any time point; however, the b/a ratio of the standard combined response was significantly higher in treated eyes than untreated eyes at 1- and 2-months PI (p=0.0092, p=0.0063). OCT: Treated Rs1-KO eyes had less severe retinoschisis at 3 weeks and 2 months PI (p=0.022, p<0.0001) compared to untreated eyes, but significance was lost at 5 months PI. VGSA: at five months after treatment, treated mice had a significantly faster time to platform than untreated mice under light adapted (cone) conditions (p=0.0024) but not in dark adapted (rod) conditions (p=0.755).
Conclusions :
Subretinal gene therapy delivering 2E9/ml AAV2/4-RS1-EF1α promoter resulted in improved cone ERG, reduced retinoschisis observed by OCT, and functional vision measured by VGSA, but no effect in rod ERG or rod mediated visual function. Patients with JXLR lose central cone function over time; our study suggests cones may be rescued separately from rods using subretinal gene therapy.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.