Biology subjects

Caggiano, A. O.

Publications and source records attributed to Caggiano, A. O..

3 recordsLinked to original sources

bioRxiv2025

Sigma-2 Receptor Modulators Alter Low-density Lipoprotein Receptor-mediated Lipid Uptake in Retinal Pigment Epithelial Cells

Lipid and photoreceptor outer segment (POS) trafficking and digestion are important homeostatic functions of retinal pigment epithelial (RPE) cells, the primary cell type that degenerates in late-stage dry AMD preceded by extracellular drusen deposits of lipids and proteins. The sigma-2 receptor (S2R, TMEM97) interacts with proteins involved in lipid trafficking, such as low-density lipoprotein receptor (LDLR), which is the primary receptor for LDL-cholesterol uptake in the retina. Preclinical studies demonstrate the necessity of S2R in protecting the retina and other nervous system tissues, and loss of either S2R or LDLR has been shown to exacerbate RPE cell death and visual dysfunction. Targeting the regulatory receptors of lipid and protein trafficking functions in RPE cells represents a tractable therapeutic strategy for dry AMD. We previously demonstrated that small molecule modulators of S2R can rescue RPE POS trafficking deficits induced by exogenous stressors. Given that disruption in lipid homeostasis is a key factor in dry AMD pathogenesis and S2R interacts with LDLR, we hypothesized that LDLR-mediated lipid trafficking in RPE could be altered using S2R-targeting small molecules. In this study, RPE cells treated with S2R modulators increased LDL uptake, assessed using fluorescently-labeled LDL, compared to vehicle-treatment. Lentiviral shRNAs to reduce TMEM97 or LDLR expression, or a neutralizing blocking antibody against LDLR, reduced S2R modulator-mediated LDL uptake, confirming the requirement of TMEM97 and LDLR for S2R modulator effects. Together, these data elaborate on a potential mechanism that may underlie the favorable reduction in geographic atrophy lesion size found in participants treated with the S2R modulator zervimensine in the Ph2 clinical trial MAGNIFY in patients with geographic atrophy (COG2201, NCT05893537). HighlightsO_LIRetinal pigment epithelial (RPE) cells express the sigma-2 receptor (S2R, TMEM97) C_LIO_LILow-density lipoprotein (LDL) uptake assay in RPE cells serves as S2R functional assay C_LIO_LIS2R modulators, including zervimesine (CT1812), increase RPE cell LDL uptake C_LIO_LIS2R modulator effects are TMEM97- and LDLR- dependent C_LI

cell biology↗

bioRxiv2025

Multi-omics comparative analyses of synucleinopathy models reveal distinct targets and relevance for drug development

BackgroundThe discovery and development of therapeutics for Parkinsons disease (PD) requires preclinical models and an understanding of the disease mechanisms reflected in each model is crucial to success. ObjectiveTo illuminate disease mechanisms and translational value of two commonly utilized rat models of synucleinopathy - AAV-delivered human mutant hA53T alpha synuclein (-Syn) and -Syn preformed fibril (PFF) injection - using a top-down, unbiased, large-scale approach. MethodsTandem mass tag mass spectrometry (TMT-MS), RNA sequencing, and bioinformatic analyses were used to assess proteins, genes, and pathways disrupted in rat striatum and substantia nigra. Comparative analyses were performed with PD drug candidate targets and an existing human PD and dementia with Lewy body (DLB) proteomics dataset. ResultsUnbiased proteomics identified 388 proteins significantly altered by hA53T--Syn and 1550 by PFF--Syn compared to sham controls. Pathway and correlation analyses of these revealed common and distinct pathophysiological processes altered in each model: dopaminergic signaling/metabolism, mitochondria and energy metabolism, and motor processes were disrupted in AAV-hA53T--Syn, while immune response, intracellular/secretory vesicles, synaptic vesicles, and autophagy were more impacted by PFF--Syn. Synapses, neural growth and remodeling, and protein localization were prominently represented in both models. Analyses revealed potential biomarkers of disease processes and proteins and pathways also altered in patients, elucidating drug targets/ disease mechanisms the models best reflect. ConclusionsAlignment of unbiased multi-omics analyses of AAV-hA53T and PFF--Syn models of synucleinopathy with PD and DLB patient data and PD drug development pipeline candidates identifies optimal models for testing novel therapeutics based on biological mechanisms.

neuroscience↗

bioRxiv2024

An interim exploratory biomarker analysis of a Phase 2 clinical trial to assess the impact of CT1812 in Alzheimers disease

CT1812 is a novel, brain penetrant small molecule modulator of the sigma-2 receptor (S2R) that is currently in clinical development for the treatment of Alzheimers disease (AD). Preclinical and early clinical data show that, through S2R, CT1812 selectively prevents and displaces binding of amyloid beta (A{beta}) oligomers from neuronal synapses and improves cognitive function in animal models of AD. SHINE is an ongoing Phase 2 randomized, double-blind, placebo-controlled clinical trial (COG0201) in patients with mild to moderate AD, designed to assess the safety and efficacy of 6 months of CT1812 treatment. To elucidate the mechanism of action in AD patients and pharmacodynamic biomarkers of CT1812, the present study reports exploratory cerebrospinal fluid (CSF) biomarker data from an interim analysis of the first set of patients in SHINE (part A). Untargeted mass spectrometry-based discovery proteomics can detect more than 2,000 proteins in patient CSF and has documented utility in accelerating the identification of novel AD biomarkers reflective of diverse pathophysiologies beyond amyloid and tau and enabling identification of pharmacodynamic biomarkers in longitudinal interventional trials. We leveraged this technique to analyze CSF samples taken at baseline and after 6 months of CT1812 treatment. Proteome-wide protein levels were detected using tandem mass tag-mass spectrometry (TMT-MS), change from baseline was calculated for each participant, and differential abundance analysis by treatment group was performed. This analysis revealed a set of proteins significantly impacted by CT1812, including pathway engagement biomarkers (i.e., biomarkers tied to S2R biology) and disease modification biomarkers (i.e., biomarkers with altered levels in AD vs. healthy control CSF but normalized by CT1812, and biomarkers correlated with favorable trends in ADAS-Cog11 scores). Brain network mapping, Gene Ontology, and pathway analyses revealed an impact of CT1812 on synapses, lipoprotein and amyloid beta biology, and neuroinflammation. Collectively, the findings highlight the utility of this method in pharmacodynamic biomarker identification and providing mechanistic insights for CT1812, which may facilitate the clinical development of CT1812 and enable appropriate pre-specification of biomarkers in upcoming clinical trials of CT1812. HIGHLIGHTSO_LIEffects of CT1812 on AD patients were investigated in a randomized Phase 2 clinical trial C_LIO_LIPharmacodynamic biomarkers of CT1812 were identified through unbiased analysis of proteomics quantitation data acquired using TMT Mass Spectrometry (TMT-MS) C_LIO_LICT1812 normalized a set of biomarkers altered in AD C_LIO_LIFindings provide proof of mechanism that CT1812 impacts synapse, inflammation, amyloid-related processes C_LI

neuroscience↗