Development of an antisense oligonucleotide targeting EFEMP1 in models relevant to macular degeneration.

Antisense oligonucleotides (ASOs) are RNA-targeting therapeutics with broad potential for genetically defined and complex ocular diseases. The eye is particularly well suited for ASO delivery because of its compartmentalized anatomy, accessibility, and capacity for sustained intraocular drug retention. Autosomal dominant drusen (ADD), an inherited retinal dystrophy characterized by early drusen formation and secondary choroidal neovascularization (CNV), is caused by the EFEMP1 R345W mutation. Mutant EFEMP1 accumulates within the retinal pigment epithelium (RPE) and extracellular matrix, contributing to disease pathology. EFEMP1 is also elevated in the serum and RPE/choroid of patients with age-related macular degeneration (AMD), although its functional role in AMD remains incompletely defined. Here, we developed a biallelic EFEMP1-targeted ASO that achieved potent knockdown and modulated disease-relevant pathways in iPSC-derived RPE, human microvascular retinal endothelial cells (HMRECs), ex vivo human choroidal explants, and in vivo mouse models. EFEMP1 protein levels were increased in AMD tissue, and ASO-mediated EFEMP1 knockdown reduced complement factor 3 (C3), suppressed HMREC proliferation and migration, and inhibited angiogenic sprouting in choroidal explants. These findings support EFEMP1 as a pathogenic regulator of retinal degeneration and vascular dysfunction and establish EFEMP1-directed ASOs as a promising therapeutic strategy for ADD and AMD.