An siRNA targeting S6k1 identifies photoreceptor phospholipid metabolism as a contributor to lipid buildup in age-related macular degeneration.

Age-related macular degeneration (AMD) remains a leading cause for visual impairment in the elderly. We recently showed that activated mammalian target of rapamycin complex 1 (mTORC1) in photoreceptor cells causes AMD-like pathologies in mouse. Employing mouse genetics, we dissect the mTORC1 pathway and identify ribosomal protein S6 kinase beta-1 (S6k1) as a key component required for disease onset in our mouse model. Using a previously identified fully chemically modified tetravalent small interefing RNA (siRNA) that enriches in photoreceptors, we target S6k1 in mouse, pigs, and non-human primates (NHP) by intravitreal injection. We find that S6k1 silencing in diseased mice reverses phospholipid changes induced by activated mTORC1, restores lysosomal activity of retinal-pigmented epithelium cells, and reduces lipoprotein buildup at Bruch's membrane (BM). In pigs, which do not develop disease, we find a similar shift in phospholipids as in mouse, indicating a conserved role for S6k1 in photoreceptor phospholipid metabolism. In aged NHPs with macular drusen, the lipoprotein-rich BM deposits that are a hallmark of human AMD, S6k1 silencing slows drusen growth over a 6-month period. These findings establish S6k1 as modifier of lipoprotein buildup at the BM and support our siRNA platform as a potential treatment modality for AMD and other retinal diseases.