June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
Transcriptomic comparison of in vitro and in vivo models for retinal dystrophy
Author Affiliations & Notes
  • Melissa Kaye Jones
    Genentech, Inc., California, United States
  • Luz Orozco
    Genentech, Inc., California, United States
  • Han Qin
    Genentech, Inc., California, United States
  • Tom Truong
    Genentech, Inc., California, United States
  • Justin Elstrott
    Genentech, Inc., California, United States
  • Zora Modrusan
    Genentech, Inc., California, United States
  • Shawnta Chaney
    Genentech, Inc., California, United States
  • Marion Jeanne
    Genentech, Inc., California, United States
  • Footnotes
    Commercial Relationships   Melissa Jones Genentech, Inc., Code E (Employment); Luz Orozco Genentech, Inc., Code E (Employment); Han Qin Genentech, Inc., Code E (Employment); Tom Truong Genentech, Inc., Code E (Employment); Justin Elstrott Genentech, Inc., Code E (Employment); Zora Modrusan Genentech, Inc., Code E (Employment); Shawnta Chaney Genentech, Inc., Code E (Employment); Marion Jeanne Genentech, Inc., Code E (Employment)
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 3198. doi:
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      Melissa Kaye Jones, Luz Orozco, Han Qin, Tom Truong, Justin Elstrott, Zora Modrusan, Shawnta Chaney, Marion Jeanne; Transcriptomic comparison of in vitro and in vivo models for retinal dystrophy. Invest. Ophthalmol. Vis. Sci. 2023;64(8):3198.

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

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Abstract

Purpose : Inherited retinal dystrophies (IRDs) are a heterogeneous group of disorders that cause photoreceptor degeneration and subsequent vision loss. Modeling IRDs in in vitro and in vivo systems have both benefits and caveats. In vitro human specific systems, such as human pluripotent stem cell (hPSC)-derived retinal organoids, may provide insight into degenerative mechanisms, but “disease-in-a-dish” models do not ideally recapitulate disease. Additionally, in vivo animal models do not have the same retinal features and may not have similar mechanisms of retinal degeneration as humans. This study evaluated the relevance of using both in vitro and in vivo models for elucidating molecular and cellular mechanisms of IRDs.

Methods : Mutations in DRAM2 are known to cause macular dystrophy; however, the underlying mechanisms are unknown. To investigate the utility of different in vitro and in vivo models of retinal dystrophy, Dram2 knockout (KO) mouse retinas and DRAM2 KO hPSC-derived retinal cells were compared. Single cell RNAseq (scRNAseq) and bioinformatics analyses of Dram2 and DRAM2 KO retinal cells were performed. To induce retinal injury, Dram2 KO mice, DRAM2 knockdown (KD) human fetal retinal pigment epithelial (RPE) cells, and DRAM2 KO hPSC-derived RPE were treated with sodium iodate, and retinal cell survival was quantified. To evaluate phagocytic capacity, wild-type and DRAM2 KO hPSC-derived RPE cells were fed photoreceptor outer segments and analyzed.

Results : Bioinformatic analysis identified similar clusters of retinal cells in Dram2 KO mouse retina and DRAM2 KO hPSC-derived retinal organoids with a portion of retinal organoid cells remaining in the progenitor state. Dram2 KO mice showed no significant difference in retinal thickness following treatment with sodium iodate; however, loss of DRAM2 in human RPE (KD and KO) caused increased susceptibility to cell death after sodium iodate treatment.

Conclusions : Comparison of Dram2 KO mouse retinas and DRAM2 KO hPSC-derived retinal organoids identified similarities in cell composition; however, key differences between mouse and human mechanisms of degeneration stress the importance for human-specific models. Loss of DRAM2 in human RPE cells increased stress-induced cell death, which may provide insight into the role of DRAM2 in retinal degeneration. In conclusion, both in vitro and in vivo models may be necessary for elucidating various mechanistic actions of IRDs.

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

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