June 2021
Volume 62, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2021
A synthetic very-long-chain polyunsaturated fatty acid (VLC-PUFA) enhances photoreceptor development in ELOVL4 knockout retinal organoids
Author Affiliations & Notes
  • Aruna Gorusupudi
    University of Utah Health John A Moran Eye Center, Salt Lake City, Utah, United States
  • Kevin Eade
    Lowy Medical Research Institute, La Jolla, California, United States
    Scripps Health, San Diego, California, United States
  • Sarah Harkins-Perry
    Lowy Medical Research Institute, La Jolla, California, United States
  • Sarah Giles
    Lowy Medical Research Institute, La Jolla, California, United States
  • Jon D Rainier
    Department of Chemistry, university of Utah, Salt Lake City, Utah, United States
  • Paul S Bernstein
    University of Utah Health John A Moran Eye Center, Salt Lake City, Utah, United States
  • Footnotes
    Commercial Relationships   Aruna Gorusupudi, University of Utah (P); Kevin Eade, None; Sarah Harkins-Perry, None; Sarah Giles, None; Jon Rainier, University of Utah (P); Paul Bernstein, University of Utah (P)
  • Footnotes
    Support  NH Grant EY14800, Foundation Fighting Blindness, Research to Prevent Blindness
Investigative Ophthalmology & Visual Science June 2021, Vol.62, 2600. doi:
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      Aruna Gorusupudi, Kevin Eade, Sarah Harkins-Perry, Sarah Giles, Jon D Rainier, Paul S Bernstein; A synthetic very-long-chain polyunsaturated fatty acid (VLC-PUFA) enhances photoreceptor development in ELOVL4 knockout retinal organoids. Invest. Ophthalmol. Vis. Sci. 2021;62(8):2600.

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

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Abstract

Purpose : Recent studies on VLC-PUFAs (C24-36) have revealed their specific presence and importance in retina. They are rarely consumed in diets and are specifically synthesized in vivo from long-chain PUFAs through the action of an enzyme known as ELOVL4. Genetic defects in ELOVL4 underlie the retinal pathology in Stargardt Type 3 (STGD3), a dominant, early-onset blinding disease with many symptoms that mirror dry age-related macular degeneration (dAMD). In a previous study, we chemically synthesized a VLC-PUFA (32:6 n-3) and measured its uptake in mouse retina and its beneficial effects on vision. In order to further study the role of VLC-PUFAs on photoreceptor development and maintenance, we supplemented 32:6 n-3 to ELOVL4 knockout retinal organoids.

Methods : We knocked out ELOVL4 in normal human iPSCs using CRIPR/Cas9 technology and generated retinal organoids using standard techniques. When the organoids had completed the phase of photoreceptor birth (17 weeks), the ELOVL4-/- organoids were divided into two groups. One group was supplemented with 8 µM 32:6 n-3, while the control group received vehicle alone. Photoreceptor outer segment morphology and length were measured at 33 weeks of age.

Results : By 33 weeks of age, the vehicle-treated ELOVL4-/- organoids had outer segments, but they appeared shorter and more disorganized than expected for normal human retinal organoids. The ELOVL4-/- organoids supplemented with 32:6 n-3 had significantly longer outer segments (P<0.001) with normal morphology.

Conclusions : These results establish that ELOVL4-/- organoids can be used as a model to study the pathophysiology and treatment of diseases associated with ELOVL4 dysfunction and that a synthetic VLC-PUFA can rescue abnormalities associated with absence of ELOVL4 activity. We are currently studying the ultrastructure of the outer segments of our treated and control organoids and the efficacies of n-3 versus n-6 VLC-PUFAs.

This is a 2021 ARVO Annual Meeting abstract.

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