June 2022
Volume 63, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2022
Altered Transcription Kinetics Drives Save or Abort Decision for Retinal Cell fate in Retinitis Pigmentosa: Reset with Modifier Gene Therapy
Author Affiliations & Notes
  • Neena B Haider
    Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States
  • Margaret M DeAngelis
    Ophthalmology, University at Buffalo, Buffalo, New York, United States
  • Footnotes
    Commercial Relationships   Neena Haider Ocugen, Code C (Consultant/Contractor); Margaret DeAngelis None
  • Footnotes
    Support  Ocugen, AMDF
Investigative Ophthalmology & Visual Science June 2022, Vol.63, 1935 – F0353. doi:
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      Neena B Haider, Margaret M DeAngelis; Altered Transcription Kinetics Drives Save or Abort Decision for Retinal Cell fate in Retinitis Pigmentosa: Reset with Modifier Gene Therapy. Invest. Ophthalmol. Vis. Sci. 2022;63(7):1935 – F0353.

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

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Purpose : Retinitis pigmentosa (RP) are a large group of genetically heterogeneous disorders that result in severe vision loss. Over 150 unique gene mutations in over 100 genes have been associated with RP, with high variability in disease onset, severity, and progression. Our prior and recent Ingenuity Pathway Analysis(IPA) revealed that Nr2e3 regulates several key biological networks that are critical to maintaining homeostasis in the retina including phototransduction, survival, apoptosis, immunity, oxidative stress, ER stress, neuroprotection and metabolism. In this study we determine the expression profiles of the key retinal transcription regulators such as Nr2e3, Nr1d1, neural retinal leucine zipper (Nrl), Cone-rod homeobox (Crx), retinoic acid receptor related orphan receptor alpha (Rora) and thyroid receptor beta (Thrb) in multiple RP models before and after treatment with AAV-Nr2e3 therapy.

Methods : Neonatal and developed rd1-/-, Rho -/-, rd16-/-, RhoP23H, and rd7 -/- AAV-Nr2e3 treated and untreated mice were euthanized and eyes were enucleated according to IACUC guidelines. RNA was isolated from retinas (N=7) at P0, P7, and P30. Gene expression profiling of key regulator genes were carried out by RNA Seq and quantitative real-time PCR.

Results : Overall, there is a significant downregulation in expression of key retina transcription factors in each model. This shift in turn causes misregulation of key homeostasis gene networks as disease progresses in each model. AAV-Nr2e3 therapy attenuates retinal degeneration and results in increased expression of key retinal transcription factors and reset of retina homeostasis.

Conclusions : This is the first report evaluating the impact of transcriptome kinetics on retinal degeneration. The primary mutation causes a shift of transcription kinetics, forcing the retina to make a save or abort decision early in disease, leading to progressive photoreceptor degeneration. This combinatorial mutational load including the primary mutation and key retinal transcription factor modulation determines phenotypic outcome of each disease. This study further shows the profound impact of AAV-Nr2e3 modifier gene therapy in attenuating retinal disease. This study uncovers how altered transcriptome kinetics impacts pathogenesis of retinal degeneration and therapeutic intervention resets these transcriptomes.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.


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