Abstract
Purpose :
Studies of both human and mouse retinas suggest declining retinal levels of very long chain (VLC) polyunsaturated fatty acids (PUFA) may play a causal role in the pathogenesis of dry AMD. The ELOVL2 enzyme plays a key role in the endogeneous biosynthesis of long chain (LC) and VLC PUFA in retina. The ELOVL2 promoter is highly susceptible to aging related methylation with a consequential down regulation of expression and decline in retinal LC and VLC PUFA. We therefore developed an AAV8-ELOVL2 gene therapy with the goal to restore physiological relevant levels of LC/VPC PUFA within the retina as a potential treatment for dry AMD.
Methods :
To determine if our experimental construct (AAV8-CB7- codon optimized human ELOVL2) could increase retinal VLC PUFA, we studied three AAV8 dosages (4E9 vg, 4E10 vg and 4E11 vg) or saline vehicle administered as a single subretinal injection to healthy African Green Monkeys (N = 5 eyes per group). 56 days after administration retina were harvested and lipidomics were determined by LC/MS.
Results :
The 4E9 vg dose was well tolerated and resulted in strong ELOVL2 expression within macular cone photoreceptors and the adjacent RPE cells as determined by qPCR and RNA scope analysis. This expression resulted in marked increases in the same VLC PUFA whose decline is associated with AMD. In addition, the increase in VLC PUFA also resulted in an increase in the ratio of omega 3/omega 6 fatty acids for the VLC PUFA measured.
Conclusions :
These results demonstrate that AAV8-ELOVL2 retinal gene therapy increases retinal levels of VLC PUFA and is an attractive strategy for treating dry AMD.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.