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

Antisense oligonucleotides (ASOs) are RNA targeting therapies with substantial potential for the medical treatment of genetically defined inherited ocular conditions and beyond. The eye is, in principle an ideal model for ASO therapeutic development due to the ease of administration and potential limited dosing frequency due to ASO durability. Autosomal dominant drusen (ADD) is an inherited retinal dystrophy characterized by early onset formation of numerous drusen with subsequent choroidal neovascularization (CNV). ADD is caused by a mutation in the epidermal growth factor-containing fibrillin-like extracellular matrix protein 1 (EFEMP1). EFEMP1R345W is expressed at high levels in the retinal pigmented epithelium (RPE) and accumulates both intracellularly and in the extracellular matrix (ECM) of the RPE during ADD. Furthermore, EFEMP1 has been reported to be significantly upregulated in serum and RPE/choroid during age-related macular degeneration (AMD) yet the consequence of EFEMP1 overexpression has not been fully elucidated. Here, we report the development of a biallelic EFEMP1 targeted ASO that has shown robust EFEMP1 knockdown and modulation of disease relevant factors in induced pluripotent stem cell-derived retinal pigment epithelium (iPSC-RPE), human microvascular retinal endothelial cells (HMREC), ex vivo human choroidal explants and in vivo mouse models. We further demonstrate that EFEMP1 is upregulated at the protein level during AMD. Herein, we report that EFEMP1 knockdown reduces complement factor 3 (C3) levels, a current target for AMD, and significantly reduces proliferation and migration in HMREC and a human choroidal explant sprouting. In summary, we propose a EFEMP1 targeted ASO as a therapeutic modality for DHRD and AMD.