June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Elamipretide Protects RPE and Improves Mitochondrial Function in Models of AMD
Author Affiliations & Notes
  • Rebecca Kapphahn
    Ophthalmology, University of Minnesota, Minneapolis, Minnesota, United States
  • Marcia Terluk
    Ophthalmology, University of Minnesota, Minneapolis, Minnesota, United States
  • Mara Ebeling
    Ophthalmology, University of Minnesota, Minneapolis, Minnesota, United States
  • Mark Pierson
    Ophthalmology, University of Minnesota, Minneapolis, Minnesota, United States
  • Kevin Mar
    Ophthalmology, University of Minnesota, Minneapolis, Minnesota, United States
  • Hwee Gong
    Ophthalmology, University of Minnesota, Minneapolis, Minnesota, United States
  • Sandra Monetzuma
    Ophthalmology, University of Minnesota, Minneapolis, Minnesota, United States
  • Yun-Zheng Le
    Endocrinology and Diabetes, Oklahoma University, Oklahoma City, Oklahoma, United States
  • Takuji Shirasawa
    Juntendo University, Tokyo, Japan
  • Takahiko Shimizu
    Chiba Univerisity, Chiba, Japan
  • Deborah A Ferrington
    Ophthalmology, University of Minnesota, Minneapolis, Minnesota, United States
  • Footnotes
    Commercial Relationships   Rebecca Kapphahn, Stealth Biotherapeutics Inc (F); Marcia Terluk, Stealth Biotherapeutics Inc (F); Mara Ebeling, Stealth Biotherapeutics Inc (F); Mark Pierson, Stealth Biotherapeutics Inc (F); Kevin Mar, Stealth Biotherapeutics Inc (F); Hwee Gong, Stealth Biotherapeutics Inc (F); Sandra Monetzuma, None; Yun-Zheng Le, None; Takuji Shirasawa, None; Takahiko Shimizu, None; Deborah Ferrington, Stealth Biotherapeutics Inc (F)
  • Footnotes
    Support  Stealth Biotherapeutics, Research to Prevent Blindness
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 1954. doi:
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      Rebecca Kapphahn, Marcia Terluk, Mara Ebeling, Mark Pierson, Kevin Mar, Hwee Gong, Sandra Monetzuma, Yun-Zheng Le, Takuji Shirasawa, Takahiko Shimizu, Deborah A Ferrington; Elamipretide Protects RPE and Improves Mitochondrial Function in Models of AMD
      . Invest. Ophthalmol. Vis. Sci. 2017;58(8):1954.

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

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Abstract

Purpose : Mitochondrial (Mt) damage and oxidative stress occur in the retinal pigment epithelium (RPE) with age-related macular degeneration (AMD). We tested the hypothesis that elamipretide (ELAM), a Mt-targeted peptide, would protect RPE from oxidative damage in primary cultures from human donors with and without AMD and in a mouse model of AMD.

Methods : Primary RPE cultures were pre-treated with ELAM then exposed to hydrogen peroxide. Cell viability, reactive oxygen species content, and Mt function (Seahorse XF Analyzer) were determined 24 hours later. ELAM-treated cells were compared with untreated cells using a paired t-test.
The RPE-specific Sod2 conditional KO mouse in which Mt manganese superoxide dismutase (MnSOD) is eliminated from the RPE was used to test the effect of daily (5 days/week) eye drops containing either 3% (w/v) ELAM or Vehicle for 12 months. Cre+ and Cre- littermates (males & females, age 2 mo) were randomly assigned to each treatment group. Changes in retinal function and structure were followed using ERG and OCT and analyzed by 2-way ANOVA. Cell size was measured in RPE whole mounts stained with ZO-1 antibody; ~900 cells/mouse were measured from 8 separate regions. The distribution of cell size was compared between groups using the Kolmogorov-Smirnov test.

Results : In the absence of peroxide, cultured RPE cells from donors with AMD (n=16) showed improved cell viability (p<0.05) and Mt function (increased ATP production, maximal respiration, spare capacity, p<0.02) relative to non-diseased donors (n=8). With peroxide, ELAM provided ~50% protection from cell death (p<0.05), reduced reactive oxygen species 30-50% (p<0.05), and generally improved Mt function in both groups.
In MnSOD KO mice, ELAM treatment had no effect on the age-dependent decrease in retinal function and changes in structure. There was a significant increase in RPE cell size in vehicle-treated Cre+ mice (n=8) compared with Cre- mice (n=9)(p<0.05), suggesting that elimination of RPE MnSOD protein induced RPE cell death. In contrast, topical ELAM treatment significantly prevented the shift to larger cell size in the Cre+ mice (n=7), suggesting fewer RPE cells died as a result of ELAM treatment.

Conclusions : ELAM’s protective effect in both human AMD donor RPE and an AMD mouse model suggest ELAM could benefit AMD patients by boosting Mt function and protecting from RPE cell loss.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

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