June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
The anti-angiogenic potential of dimethyl fumarate for wet age-related macular degeneration
Author Affiliations & Notes
  • Daisy Y Shu
    Ophthalmology, Schepens Eye Research Institute of Massachusetts Eye and Ear, Boston, Massachusetts, United States
    Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States
  • Margarete Karg
    Ophthalmology, Schepens Eye Research Institute of Massachusetts Eye and Ear, Boston, Massachusetts, United States
    Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States
  • Anton Lennikov
    Ophthalmology, Schepens Eye Research Institute of Massachusetts Eye and Ear, Boston, Massachusetts, United States
    Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States
  • Suman Chaudhary
    Ophthalmology, Schepens Eye Research Institute of Massachusetts Eye and Ear, Boston, Massachusetts, United States
    Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States
  • Leo A Kim
    Ophthalmology, Schepens Eye Research Institute of Massachusetts Eye and Ear, Boston, Massachusetts, United States
    Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States
  • Footnotes
    Commercial Relationships   Daisy Shu None; Margarete Karg None; Anton Lennikov None; Suman Chaudhary None; Leo Kim eNano and the application of Ro24 as an antifibrotic in the lungs, Code P (Patent)
  • Footnotes
    Support  DYS is funded by the BrightFocus Foundation Postdoctoral Fellowship Program in Macular Degeneration Research. LAK is supported by the National Eye Institute of the National Institutes of Health under Award no. R01EY027739 and the Iraty Award.
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 2127. doi:
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    • Get Citation

      Daisy Y Shu, Margarete Karg, Anton Lennikov, Suman Chaudhary, Leo A Kim; The anti-angiogenic potential of dimethyl fumarate for wet age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 2023;64(8):2127.

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

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Abstract

Purpose : Wet age-related macular degeneration (AMD) is characterized by aberrant angiogenesis which disturbs the well-organized choroidal vasculature. The newly formed vessels are leaky and immature leading to edema, further inflammation, and ultimate tissue dysfunction. We previously showed that dimethyl fumarate (DMFu) exhibited anti-inflammatory properties in retinal pigment epithelial cells. Here, we investigated the anti-angiogenic potential of DMFu in human retinal microvascular endothelial cells and mouse choroidal explants. Since DMFu is an FDA-approved oral drug, it serves as a contender for drug repurposing and rapid clinical implementation for AMD treatment.

Methods : Human retinal microvascular endothelial cells (HRECs, Cell Systems) were cultured in Endothelial Basal Media-2 (EBM-2) BulletKit Medium (Lonza, #CC-3162) at 37°C with 5% CO2. The migratory capacity of HRECs was examined using the scratch wound assay. Confluent HRECs were starved for 8 h in serum-free EBM-2 before mechanical scratching with a p200 pipette tip in serum-free EBM-2 with/without VEGF (10 ng/ml) and DMFu (80 μM). Changes in gene expression of the pro-inflammatory cytokine, interleukin-6 (IL-6), was assessed using qPCR. For the choroidal sprouting assay, 1 mm2 punch biopsies of RPE/choroid/sclera were collected from the peripheral region of the posterior cup from 3-week-old C57BL/6J mice (male and female) and embedded in 30 µL of Cultrex BME in 24-well tissue culture plates. Images were taken on the EVOS M7000 Live Cell Imaging System and analyzed using Image J.

Results : Concurrent addition of DMFu significantly reduced endothelial cell migration at 20 hours even in the presence of VEGF, highlighting the anti-angiogenic potential of DMFu in HRECs. While VEGF did not change IL-6 levels compared to untreated HRECs, DMu suppressed basal levels of IL-6, supporting its established anti-inflammatory activity. The anti-angiogenic potential of DMFu was further demonstrated using the ex vivo choroidal sprouting assay. VEGF induced a dramatic sprouting response compared to the control as expected. Concurrent addition of DMFu robustly inhibited VEGF-induced choroidal sprouting and DMFu alone also inhibited choroidal sprouting.

Conclusions : Our data highlight that the metabolic drug, DMFu, has both anti-inflammatory and anti-angiogenic effects on endothelial cells, thus serving as a promising therapeutic for the treatment of wet AMD.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

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