June 2022
Volume 63, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2022
Use of iPSC-derived RPE to test the efficacy of elamipretide and SBT-272 in preclinical models of dry AMD
Author Affiliations & Notes
  • Mark Anthony Fields
    Ophthalmology, Yale School of Medicine, New Haven, Connecticut, United States
  • Jie Gong
    Ophthalmology, Yale School of Medicine, New Haven, Connecticut, United States
  • Huey Cai
    Ophthalmology, Yale School of Medicine, New Haven, Connecticut, United States
  • Lucian Del Priore
    Ophthalmology, Yale School of Medicine, New Haven, Connecticut, United States
  • Footnotes
    Commercial Relationships   Mark Fields Stealth BioTherapeutics, Code C (Consultant/Contractor), Stealth BioTherapeutics, Code F (Financial Support); Jie Gong None; Huey Cai None; Lucian Del Priore Stealth BioTherapeutics, Code C (Consultant/Contractor)
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2022, Vol.63, 4624 – F0416. doi:
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    • Get Citation

      Mark Anthony Fields, Jie Gong, Huey Cai, Lucian Del Priore; Use of iPSC-derived RPE to test the efficacy of elamipretide and SBT-272 in preclinical models of dry AMD. Invest. Ophthalmol. Vis. Sci. 2022;63(7):4624 – F0416.

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      © ARVO (1962-2015); The Authors (2016-present)

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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.

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