iPSC-Based Disease Modeling Studies Reveal Common Mechanistic Defect and Potential Therapies for AMD and Related Macular Dystrophies

Abstract

Age-related macular degeneration (AMD) and related macular dystrophies (MDs) primarily affect the retinal pigment epithelium (RPE) in the eye. A primary hallmark of AMD/MDs that drives later stage pathologies of maculopathies is drusen. However, how drusen forms and accumulates is not known. We demonstrate that reduced activity of RPE-secreted matrix metalloproteinase 2 (MMP2) contributes to drusen accumulation in multiple maculopathies in a genotype-agnostic manner. Specifically, reduced levels of RPE-secreted MMP2 promotes several pro-maculopathy changes including drusen by promoting sterile inflammation and impaired lipid homeostasis via activation of i) receptor for advanced glycation end-products (RAGE) and ii) secretory phospholipase 2-IIA (sPLA2-IIA). Therapeutically, RPE-specific MMP2 supplementation, RAGE antagonistic peptide and a small molecule inhibitor of sPLA2-IIA ameliorated drusen accumulation in iPSC model(s) of AMD and 3 distinct MDs. Altogether, we define a causal role of MMP2-RAGE-sPLA2-IIA axis in macular degeneration and pharmacologically target the disease phenotype in patient-relevant iPSC model(s) of AMD/MDs.

Note:

Funding Information: This work was supported by R01EY028167 (R.S.), R01EY030183 (R.S.), R01EY033192 (R.S.), R21EY030817 (R.S.), R01EY027083 (BAA), P30EY025585 (BAA), funding from ForeBatten Foundation, Research to Prevent Blindness, RPB’s Career Development Award (R.S.) and Unrestricted Challenge Grant to Department of Ophthalmology at University of Rochester and Cleveland Clinic Foundation, Cleveland Eye Bank Foundation Award (Cole Eye Institute), Cleveland Clinic Unrestricted Funds (BA-A) and University Research Award given to R.S. by the University of Rochester.

Declaration of Interests: The authors declare no conflict of interest.

Ethics Approval Statement: Fibroblasts/human iPSC procurement and usage was approved by the University of Rochester’s institutional regulatory board. Deidentified patient samples and donor tissue were used in this study under the approval of Institutional Regulatory Board (IRB) at the University of Rochester and confirmed with the ethical norms and declaration of Helsinki.

Keywords: Age-related macular degeneration, macular dystrophy, drusen, sterile inflammation, retinal pigment epithelium, tissue inhibitor of metalloproteinase 3, matrix metalloproteinase 2.