Abstract
Purpose :
Identification of compounds that may be of therapeutic benefit in inhibiting progression of AMD is limited by the absence of good animal models as well as a clear understanding of the biology of disease progression. Dysfunction of retinal pigment epithelial (RPE) cells is a key feature of AMD pathogenesis and likely occurs early in the disease. Somatic cells harvested from AMD patients can be reprogrammed to form RPE and model patient-specific disease. We have reported previously that iPSC-derived RPE from AMD patients exhibit a retinal degenerative phenotype and a distinct transcriptome compared to controls. Here, we use an in vitro aged Bruch’s membrane model to evaluate the therapeutic efficacy of elamipretide and SBT-272 on RPE derived from AMD patients.
Methods :
iPSC-derived RPE were generated from AMD patients (2 atrophic; 1 exudative) and patients with no history of AMD (n = 3). To test the therapeutic efficacy of elamipretide and SBT-272, cell viability was analyzed on nitrite-modified extracellular matrix (ECM), a typical modification of aged Bruch's membrane, for 48 hrs. DNA microarrays were used to elucidate gene expression in AMD-derived RPE cultured on nitrite-modified ECM.
Results :
AMD-derived RPE exhibited reduced ability to survive on nitrite-modified ECM. Treatment with both elamipretide and SBT-272 significantly improved cell viability on nitrite-modified ECM. Hierarchical clustering analysis reveals that the AMD-derived RPE segregate into two distinct clusters on nitrite-modified ECM vs. unmodified ECM. Nitration of ECM increases expression of complement component genes, complement C1R (C1R), complement component 3 (C3) and complement C4A (C4A), among others. Both compounds reverse this trend. Both drugs increase expression of complement regulatory genes including complement factor H-related protein 2 (CFHR2). Both drugs also alter the pattern of many mitochondrial-related genes such as glutaminase.
Conclusions :
Treatment with elamipretide and SBT-272 significantly improve the ability of AMD-derived RPE to survive on nitrite-modified ECM. Treatment with elamipretide and SBT-272 alter expression of mitochondrial and complement-related genes after nitration of ECM. Disease models using patient-derived iPSC-derived RPE may help pave the way for the development novel therapeutic strategies for AMD.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.