Sigma-2 receptor modulator CT1812 alters key pathways and rescues retinal pigment epithelium (RPE) functional deficits associated with dry age-related macular degeneration (AMD)

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: Feb. 10, 2025

Trafficking defects in retinal pigmented epithelial (RPE) cells contribute to RPE atrophy, a hallmark of geographic atrophy (GA) dry age-related macular degeneration (AMD). Dry AMD pathogenesis is multifactorial, including amyloid-β (Aβ) accumulation and oxidative stress-common features Alzheimer's disease (AD). The Sigma-2 receptor (S2R) regulates lipid protein trafficking, S2R modulators reverse trafficking deficits neurodegeneration vitro models. Given overlapping mechanisms contributing AD AMD, modulator effects on function were investigated. CT1812 clinical trials for AD, dementia with Lewy bodies, GA. Leveraging testing CT1812, unbiased analyses patient biofluid proteomes revealed that proteins altered by associated GA ontologies overlapped AMD. Differential expression analysis transcripts from APP-Swedish/London mutant transgenic mice, model featuring Aβ accumulation, reversal autophagy/trafficking modulator-treated animals versus vehicle toward healthy control levels. Photoreceptor outer segment (POS) human showed response Aβ1-42 or hydrogen peroxide compared vehicle. normalized stressor-induced POS deficits, resembling control. Taken together, modulation may provide novel therapeutic strategy

Language: Английский

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CT1812 biomarker signature from a meta‐analysis of CSF proteomic findings from two Phase 2 clinical trials in Alzheimer's disease

Alzheimer s & Dementia, Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 21, 2024

Abstract INTRODUCTION CT1812 is in clinical development for the treatment of Alzheimer's disease (AD). Cerebrospinal fluid (CSF) exploratory proteomics was employed to identify pharmacodynamic biomarkers mild moderate AD from two independent trials. METHODS Unbiased analysis tandem‐mass tag mass spectrometry (TMT‐MS) quantitative proteomics, pathway and correlation analyses with volumetric magnetic resonance imaging (vMRI) were performed SPARC cohort (NCT03493282). Comparative a meta‐analysis interim SHINE (NCT03507790; SHINE‐A) followed by network (weighted gene co‐expression [WGCNA]) used understand biological impact CT1812. RESULTS pathways identified that replicate across cohorts. The revealed novel candidate linked S2R biology AD, treatment‐associated networks driven S2R. DISCUSSION Early validation replicating cohorts strengthens understanding patients supports CT1812's synaptoprotective mechanism action its continued development. Highlights This study (NCT03493282) trials/cohorts Two Ph2 trial (SPARC [NCT03507790; SHINE‐A]) Amyloid beta (Aβ) & synaptic impacted treatment‐related correlates emerge Network sigma‐2 receptor (S2R)‐interacting proteins may be “drivers” changes

Language: Английский

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A Pilot Electroencephalography Study of the Effect of CT1812 Treatment on Synaptic Activity in Patients with Mild to Moderate Alzheimer’s Disease

The Journal of Prevention of Alzheimer s Disease, Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 1, 2024

Language: Английский

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Comparison of the efficacy of updated drugs for the treatment on the improvement of cognitive function in patients with Alzheimer ’s disease: A systematic review and network meta- analysis

Neuroscience, Journal Year: 2024, Volume and Issue: 565, P. 29 - 39

Published: Nov. 15, 2024

Language: Английский

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Neuroprotective Effect of Sigma-2 Modulator CT2074 in a Mouse Model of Ocular Hypertension

Experimental Eye Research, Journal Year: 2024, Volume and Issue: 249, P. 110143 - 110143

Published: Oct. 30, 2024

Language: Английский

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