Abstract
Purpose :
CT1812, now in Ph2 clinical trials for Alzheimer’s disease (AD), is an orally bioavailable, brain penetrant small molecule antagonist of the sigma-2 receptor, which contributes to key pathways involved in age-related diseases including autophagy, lipid trafficking, and amyloid-β (Aβ) toxicity. Human genetics points to a role of the sigma-2 receptor in dry age-related macular degeneration (dAMD); namely, a SNP in the chief sigma-2 receptor constituent TMEM97 locus confers an increased risk for dAMD (Fritsche et al., 2016). In support, CRISPR knockdown of TMEM97 in retinal pigment epithelial (RPE) cells significantly ameliorates oxidative stress-triggered cell death (Wang et al., 2020). We hypothesized that CT1812 will alter dAMD-relevant biologies in patients and in human iPSC-RPE cells treated with disease-relevant stressors.
Methods :
Proteomics analysis was performed with plasma and cerebrospinal fluid (CSF) from AD patients treated with CT1812 or placebo for 28 day (N=14) or 6 mo (N=18). Unbiased pathway analyses were performed using Metacore to identify the pathways significantly altered in AD patients treated with CT1812 compared to placebo, and data were compared to publicly available dAMD proteomic datasets to identify significantly altered proteins linked to dAMD. Human iPSC-RPE cells were exposed to hydrogen peroxide, TNF-α and IFN-γ, Aβ oligomers, or vehicle to assess the effect of CT1812 under physiological and pathophysiological conditions. RNAseq analysis, including differential expression and pathway analysis, was performed to evaluate the transcriptomic changes elicited by CT1812 in vehicle- or stressor-treated cultures.
Results :
Unbiased pathway analysis of AD clinical trial CSF proteomics indicated that geographic atrophy was the most significantly altered functional disease ontology by CT1812 compared to placebo (p<0.05), and comparative analyses to publicly available AMD datasets illuminated a subset of dAMD-relevant proteins altered by CT1812 (p<0.05). In iPSC-RPEs (n=3-4), transcriptomic analyses revealed highly regulated genes and pathways (p<0.05) altered by oxidative stress, inflammation, and Aβ oligomers and by CT1812 vs vehicle data, illuminating the role of sigma-2 signaling in RPE cells under physiological and pathophysiological conditions.
Conclusions :
In sum, data indicate a key role of sigma-2 in AMD and suggest CT1812 may be a promising therapeutic approach for dAMD.
This is a 2021 ARVO Annual Meeting abstract.