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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE289976 | GEO | 2026/08/03

REPOSITORIES: GEO

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Project description:Background: Age-related macular degeneration (AMD) is caused by the degeneration of the macular photoreceptors. This is preceded by development of subretinal protein aggregates (drusen) and degeneration of the macular retinal pigment epithelium (RPE). The underlying pathogenesis remains unknown, but the immune system is suspected to play a key role in it. Aging of the immune system, immunosenescence, includes changes in T cell sub-populations and results in low-level chronic inflammation. Because AMD exclusively occurs in patients over 55 years of age, we hypothesize that aging of the T cell compartment may be implicated in AMD pathogenesis. Methodology and principal findings: Using an in vitro co-culture system, we investigated the effects of activated T cells on a human RPE cell line (ARPE-19). Differential gene expression in the RPE cells of complement factor genes was identified using microarrays, and selected gene transcripts from the alternative complement pathway were validated by q-RT-PCR. Protein expression was determined by ELISA and immunoblotting. Co-culture with activated T cells increased RPE mRNA and protein expression of complement component C3, factors B, H, H-like 1, CD46, CD59, and clusterin, in a dose-dependent manner. Conclusions: RPE cells responded to inflammatory assault caused by exposure to T cell-derived cytokines by upregulating expression of many complement factors from the alternative pathway. This may have implications for RPE ability to deal with complement attack, and opsonization and removal of debris from the RPE-choroidal interface. We speculate that regulation of the complement system in response to inflammatory assault may play a vital role in RPE pathology and drusen biogenesis. Experiment Overall Design: 10 samples investigating variations of co-cultures of RPE cells and T-cells. Variable parameters include the cell type, the co-culturing of the counter-part cell type and the orientation of the system (apical vs basolateral).

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

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