biostudies-literatureDalvi SNational Eye InstituteNEI NIH HHSResearch to Prevent BlindnessUniversity of RochesterCleveland ClinicNational Institutes of HealthUniversity of Rochester School of Medicine and DentistryNIH HHS3290-3305.e9https://www.ebi.ac.uk/biostudies/studies/S-EPMC11652237biostudies-literatureUnknown59(24)Age-related macular degeneration (AMD) and related macular dystrophies (MDs) primarily affect the retinal pigment epithelium (RPE) in the eye. A hallmark of AMD/MDs that drives later-stage pathologies is drusen. Drusen are sub-RPE lipid-protein-rich extracellular deposits, but how drusen forms and accumulates is not known. We utilized human induced pluripotent stem cell (iPSC)-derived RPE from patients with AMD and three distinct MDs to demonstrate that reduced activity of RPE-secreted matrix metalloproteinase 2 (MMP2) contributes to drusen in multiple maculopathies in a genotype-agnostic manner by instigating sterile inflammation and impaired lipid homeostasis via damage-associated molecular pattern molecule (DAMP)-mediated activation of receptor for advanced glycation end-products (RAGE)Developmental cellHuman iPSC-based disease modeling studies identify a common mechanistic defect and potential therapies for AMD and related macular dystrophies.PMC11652237P30 EY025585R01EY027083R21EY030817R01EY033192R21 EY030817P30EY025585R01 EY030183R01EY030183S10 OD030302R01 EY027083R01 EY033192R01 EY028167R01EY028167Spencer WDalvi SChatterjee ABhogavalli ABharti KAnand-Apte BReuben-Thomas CRoll MKumar LKPebay AFoley NSingh RArduino COrtolan DfalseHuman iPSC-based disease modeling studies identify a common mechanistic defect and potential therapies for AMD and related macular dystrophies.Age-related macular degeneration (AMD) and related macular dystrophies (MDs) primarily affect the retinal pigment epithelium (RPE) in the eye. A hallmark of AMD/MDs that drives later-stage pathologies is drusen. Drusen are sub-RPE lipid-protein-rich extracellular deposits, but how drusen forms and accumulates is not known. We utilized human induced pluripotent stem cell (iPSC)-derived RPE from patients with AMD and three distinct MDs to demonstrate that reduced activity of RPE-secreted matrix metalloproteinase 2 (MMP2) contributes to drusen in multiple maculopathies in a genotype-agnostic manner by instigating sterile inflammation and impaired lipid homeostasis via damage-associated molecular pattern molecule (DAMP)-mediated activation of receptor for advanced glycation end-products (RAGE)2024-01-01T00:00:00Z2024 Dec2026-06-13T04:47:45.529Z2026-06-13T03:08:54.43ZS-EPMC116522373936222010.1016/j.devcel.2024.09.006