June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
9-cis-β-Carotene rescues cones and reduces retinal microglial cell activation
Author Affiliations & Notes
  • Ifat Sher-Rosenthal
    Goldschleger Eye Institute, Sheba Medical Center, Tel Hashomer, Tel Aviv, Israel
    Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
  • Margalit Altman
    Goldschleger Eye Institute, Sheba Medical Center, Tel Hashomer, Tel Aviv, Israel
    Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
  • Emily Praisman
    Goldschleger Eye Institute, Sheba Medical Center, Tel Hashomer, Tel Aviv, Israel
  • Sara Pri-Chen
    Goldschleger Eye Institute, Sheba Medical Center, Tel Hashomer, Tel Aviv, Israel
  • Sharon Gilad
    BLAVATNIK CENTER for Drug Discovery, Tel Aviv University, Tel Aviv, Israel
  • Ludmila Buzhansky
    BLAVATNIK CENTER for Drug Discovery, Tel Aviv University, Tel Aviv, Israel
  • Rachel Grinberg
    Strassburger Lipid Center, Sheba Medical Center, Tel Hashomer, Tel Aviv, Israel
  • Aviv Shaish
    Strassburger Lipid Center, Sheba Medical Center, Tel Hashomer, Tel Aviv, Israel
  • Ehud Gazit
    BLAVATNIK CENTER for Drug Discovery, Tel Aviv University, Tel Aviv, Israel
  • Ygal Rotenstreich
    Goldschleger Eye Institute, Sheba Medical Center, Tel Hashomer, Tel Aviv, Israel
    Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
  • Footnotes
    Commercial Relationships   Ifat Sher-Rosenthal Sheba Medical Center, Code P (Patent); Margalit Altman None; Emily Praisman None; Sara Pri-Chen None; Sharon Gilad Tel Aviv University, Code P (Patent); Ludmila Buzhansky Tel Aviv University, Code P (Patent); Rachel Grinberg None; Aviv Shaish Sheba Medical Center, Code P (Patent); Ehud Gazit Tel Aviv University, Code P (Patent); Ygal Rotenstreich Sheba Medical Center, Code P (Patent)
  • Footnotes
    Support  SPARK Tel Aviv
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 2593. doi:
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    • Get Citation

      Ifat Sher-Rosenthal, Margalit Altman, Emily Praisman, Sara Pri-Chen, Sharon Gilad, Ludmila Buzhansky, Rachel Grinberg, Aviv Shaish, Ehud Gazit, Ygal Rotenstreich; 9-cis-β-Carotene rescues cones and reduces retinal microglial cell activation. Invest. Ophthalmol. Vis. Sci. 2023;64(8):2593.

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

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Abstract

Purpose : In previous preclinical and clinical studies, we demonstrated that oral treatment with the 9-cis β-carotene (9CBC)-rich Dunaliella alga significantly improved retinal function in RP patients and patients with mutations in RDH5, a visual cycle enzyme. In vivo oral treatment with the alga extract rescued retinal function and promoted photoreceptor survival in RPE65/rd12 mice, suggesting that 9CBC, a 9-cis-retinal precursor, may present a promising safe treatment strategy for RP associated with visual cycle defects. Despite the success of these studies, the alga-based treatment is not a viable option as algae 9CBC content has dramatically decreased in the last decades, and is far below therapeutic levels. We developed a novel, convenient and cost-effective synthetic route for 9CBC. The aim of this research was to develop biologically active synthetic 9CBC formulations and to characterize the 9CBC mode of action.

Methods : Eye caps of RPE65/rd12 mice were incubated in media supplemented with natural and synthetic 9CBC, all-trans-beta carotene (ATBC) or vehicle for 18 hours. Retinas were fixed and sections were stained with antibodies directed against S-cone opsin and M-cone opsin. The number of positively stained cells per retinal section was determined. The potency of 9CBC to reduce microglia cell activation was determined in primary RCS rat retinal microglial cell cultures.

Results : 1μM synthetic 9CBC enhanced S- and M-cone survival in RPE65/rd12 eyecups in-vitro by 2-folds (p=0.001) and 4-folds (p=0.009) respectively, compared to placebo. A similar rescue level was obtained by the alga-derived 9CBC. By contrast, supplementing the media with 1mM all-trans beta carotene resulted in a nearly 2-fold lower cone survival compared with placebo treatment. 9CBC treatment reduced the size of LPS-activated microglial cells by 1.77 folds (p<0.0001 compared with placebo treatment), to a level similar to that of non-activated cells.

Conclusions : Synthetic 9CBC effectively increased cone survival, with similar efficacy as natural 9CBC. In addition to supporting photoreceptor survival, 9CBC may alleviate retinal degeneration by reducing retinal microglia activation. This study suggests that synthetic 9CBC may present a potential treatment for retinoid-cycle associated retinal degeneration.

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

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