Researchers at the Department of Ophthalmology, and the Center for Visual Science, University of Rochester, New York, have reported a study using induced pluripotent stem cells (iPSC cells) to model AMD, and other maculopathies, which has shown that impaired metalloproteinases (MMPs) may lead to drusen formation. In addition, a therapeutic approach that includes a small molecule inhibitor (sPLA2-IIA) may block inflammation and ameliorate drusen, potentially improving the conditions. MMP supplementation, an antagonist peptide and the sPLA2-IIA inhibitor could provide a new strategy to target certain late-stage AMD pathologies. The lead author of the study, Ruchira Singh, PhD, at the University of Rochester, stated that, “if we can halt the accumulation of drusen, we may be able to prevent the disease from progressing to a stage where vision loss occurs. This research offers hope for developing new treatments that could significantly improve the lives of millions of people affected by AMD.”
Ruchira Singh, PhD, with the University of Rochester Flaum Eye Institute and Center for Visual Sciences.
In their study, the researchers used human iPSC-derived RPE from patients with AMD, and three distinct macular dystrophies – Sorsby’s fundus dystrophy (SFD), Doyne honeycomb macular dystrophy (DHRD) and autosomal dominant radial drusen (ADRD). The modelling of their work showed that an accumulation of tissue inhibitor of metalloproteinases 3 (TIMP3) caused a decrease of matrix metalloproteinases (MMPs) and this was sufficient to instigate AMD and macular dystrophies, contributing to drusen formation and RPE atrophy. According to the researchers, the iPSC technology has “provided a unique platform to investigate disease pathobiology in patient-relevant cell models” and these models “can faithfully recapitulate important pathological aspects of retinal degenerative diseases.” Reduced activity of metalloproteinases has also been linked to other inflammatory conditions, including arthritis and atherosclerosis.
To therapeutically address the pathology, the researchers used MMP supplementation, an antagonist peptide (targeting a receptor for advanced glycation end-products) and the small molecule inhibitors of sPLA2-IIA (secretory phospholipase 2-IIA) and this may reduce the drusen accumulation in AMD and macular dystrophy models. Their study, published in Developmental Cell (59, 1–16, December 16, 2024), concluded that, “utilizing small molecules to target drusen, a key driver of late-stage AMD/MD pathologies, bodes well for successful drug-based therapy of these blinding diseases.” In their study, the researchers noted that the University of Rochester has filed a provisional US patent application, for U.S. Provisional Patent Application No. 63/632,123, filed April 10, 2024, with a title of: ‘‘Drug Treatment for Macular Degeneration.’’