Abstract
Purpose :
Dysregulated lipid homeostasis and local lipid accumulation are associated with many age-related diseases, including age-related macular degeneration (AMD), which is a leading cause of blindness in the elderly. We have identified a pathological lipid modulating microRNA, miR-33 previously. Its expression is elevated in the retinal pigment epithelial (RPE) of aging mice and regulated downstream target ATP-binding cassette transporter (ABCA1) level, cholesterol efflux, and lipid accumulation in AMD pathogenesis. Additionally, antisense oligonucleotides (ASO) targeting miR-33 in aging mice and non-human primates fed a western diet ameliorated phenotypes linked to AMD through anti-miR-33 subcutaneously delivery. In this study, we assessed the efficacy of local delivery by intravitreal injection in aging mice.
Methods :
Twelve-month-old C57BL/6J mice were purchased from Jackson Laboratory and fed a WTD supplemented with 40% kcal from milkfat (Research Diets, D12079B) for 4 weeks prior to and during treatment. Intraviteal injecitons were used to delivere the anti-miR-33 ASO, scramble ASO was used as control in the contralateral eye. Mice were sacrificed 72 h after the last injection. Eyes were enucleated for RNA, protein extraction from RPE cells, cryosectioning, electron microscopy and lipidomic analyses.
Results :
Our data suggested single intravitreal injection of anti-miR-33 ASO in aged mice fed a Western-type diet was safe and well-tolerated. We have observed elevated ABCA1 expression in the RPE, significantly decreased microglia-macrophage (Iba1) activation and decreased Bruch’s membrane derangements.
Conclusions :
Taken together, these findings suggest that anti-miR-33 ASO could be a potential therapeutic approach to ameliorate AMD initiation and progression.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.