June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
Unbiased transcriptomic analysis of the sigma-2 receptor modulator CT1812 in cell-based models of dry age-related macular degeneration
Author Affiliations & Notes
  • Britney N Lizama
    Cognition Therapeutics Inc, Pittsburgh, Pennsylvania, United States
  • Lora Waybright
    Cognition Therapeutics Inc, Pittsburgh, Pennsylvania, United States
  • Evi Malagise
    Cognition Therapeutics Inc, Pittsburgh, Pennsylvania, United States
  • Emily Watto
    Cognition Therapeutics Inc, Pittsburgh, Pennsylvania, United States
  • Anthony Caggiano
    Cognition Therapeutics Inc, Pittsburgh, Pennsylvania, United States
  • Mary E Hamby
    Cognition Therapeutics Inc, Pittsburgh, Pennsylvania, United States
  • Footnotes
    Commercial Relationships   Britney Lizama None; Lora Waybright None; Evi Malagise None; Emily Watto None; Anthony Caggiano None; Mary Hamby None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 2119. doi:
  • Views
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to authenticated users only.
      Sign In or Create an Account ×
    • Get Citation

      Britney N Lizama, Lora Waybright, Evi Malagise, Emily Watto, Anthony Caggiano, Mary E Hamby; Unbiased transcriptomic analysis of the sigma-2 receptor modulator CT1812 in cell-based models of dry age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 2023;64(8):2119.

      Download citation file:


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

      ×
  • Supplements
Abstract

Purpose : CT1812 is an orally bioavailable, brain-penetrant small molecule sigma-2 receptor (S2R) modulator in Phase 2 clinical trials for Alzheimer’s disease and dementia with Lewy bodies. S2R contributes to key pathways involved in age-related diseases including oxidative stress, autophagy, and amyloid-beta (Aβ) toxicity. A single nucleotide polymorphism (SNP) in the chief S2R constituent TMEM97 locus confers a decreased risk for dry age-related macular degeneration (AMD). Given the overlap in S2R-regulated pathways and dry AMD pathology, the ability to rescue key functional deficits in retinal pigment epithelial (RPE) cells, and the genetic link of S2R to dry AMD, it was hypothesized that the S2R modulator CT1812 will alter dry AMD-relevant transcripts and pathways.

Methods : To further understand the effects of CT1812 under physiological and pathophysiological conditions, two RPE cell culture models – human iPSC-RPE cells and polarized ARPE-19 cells – were exposed to the toxic protein Aβ oligomers, the oxidative stressor hydrogen peroxide, or medium alone (untreated), with or without CT1812. Cultures were harvested for total RNA after 8 hours of treatment, and RNA sequencing was performed to evaluate how CT1812 affected the transcriptomic phenotype in stressor-treated cultures. To this end, differential gene expression analysis, STRING and MetaCore pathway analyses were performed.

Results : In iPSC-RPE and ARPE-19 cells, differential expression and pathway analyses identified mRNA transcripts and biological pathways significantly altered (p<0.05) by Aβ oligomers or hydrogen peroxide that are relevant to dry AMD pathogenesis. In both models and stressor conditions, CT1812 altered (p<0.05) key mRNA transcripts and biological pathways involved in immune response, extracellular matrix remodeling, and cell survival. Further comparative analysis was performed to identify transcripts commonly altered between the RPE culture models. While some expression changes were cell model-specific, a subset of transcripts were found to be commonly altered across models.

Conclusions : Overall, these data shed light on the mechanisms by which CT1812 and S2R act in disease-relevant models of dry AMD. While additional studies are underway to validate the signaling pathways identified by our transcriptomics analysis, this study supports further investigation of S2R modulators for dry AMD.

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

×
×

This PDF is available to Subscribers Only

Sign in or purchase a subscription to access this content. ×

You must be signed into an individual account to use this feature.

×