Abstract Details

Title Integrated Genomic, Proteomic, and Transcriptomic Profiling Support Cathepsin-B as a Drug Repurposing Target in Cerebral Small Vessel Disease

Topic Cerebrovascular Disease and Interventional Neurology

Presentation(s) S2 - Advances in Stroke Imaging and Biomarkers (1:00 PM-1:12 PM)

Poster/Presentation
Number 001

Objective Integrate genomic, proteomic, and transcriptomic data to identify proteins that may target and slow the progression of White Matter Hyperintensities (WMH).

Background WMH, a radiographic indicator of Cerebral Small Vessel Disease (CSVD) and a determinant of stroke and dementia, currently lacks specific drug targets. Particularly promising are proteins serving as pathway-level hubs through which polygenic effects converge.

Design/Methods

We analyzed data from 53,014 UK Biobank participants using the following pipeline: 1)association analyses between a polygenic risk score of WMH and 2,923 protein levels; 2)evaluation of proteins selected in step 1 for association with WMH volume, ascertained through research MRIs; 3)mediation analyses to confirm that proteins with significant and directionally concordant associations with both the polygenic score and WMH are indeed mediators of the polygenic score-WMH relationship; 4)Mendelian Randomization using cis-protein quantitative trait loci to evaluate causality between selected proteins and WMH and other CSVD traits. Additionally, differential expression was examined in single-nucleus RNA sequencing from WMH lesions in four vascular dementia patients and four controls.

Results Cathepsin B (CTSB) was the sole protein meeting all the criteria. Mendelian Randomization confirmed CTSB’s association with WMH (β:−0.092, SE:0.003, P<0.001) and other CSVD traits: intracerebral hemorrhage, small vessel stroke, perivascular space volume, and white matter microstructure changes. In alignment with CTSB’s protective effect on CSVD, CTSB expression was significantly reduced in astrocytes (log2FC:−1.7, adj.p<0.0001), oligodendrocytes (log2FC:−0.48, adj.p<0.0001), and microglia (log2FC:−0.35, adj.p<0.0001) of WMH lesions compared to healthy white matter.

Conclusions Our combined multi-omics approach identified CTSB as a protein protective for WMH and other CSVD phenotypes. CTSB, a lysosomal protease involved in the autophagy-lysosomal pathway is well-known for its involvement in hypoxia/ischemia-induced neuronal death, a key mechanism leading to WMH. Compounds targeting CTSB have shown promise in reducing neuronal death in Alzheimer’s models, suggesting potential for repurposing to stabilize WMH and reduce subsequent stroke and dementia risk.

Authors/Disclosures
Cyprien Rivier, MD (Yale University) PRESENTER	Dr. Rivier has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Pyxis Partners.
Shufan Huo, MD, PhD (Yale University)	Dr. Huo has nothing to disclose.
Santiago Clocchiatti-Tuozzo (Yale University, Department of Neurology)	Mr. Clocchiatti-Tuozzo has nothing to disclose.
Daniela B. Renedo, MD (Yale University)	Dr. Renedo has nothing to disclose.
Richa Sharma, MD (Massachusetts General Hospital, Brigham, Harvard)	Dr. Sharma has received research support from NIH. Dr. Sharma has received intellectual property interests from a discovery or technology relating to health care.
Sam Payabvash	Sam Payabvash has nothing to disclose.
Srikant Rangaraju, MBBS (Emory University, Atlanta)	Dr. Rangaraju has nothing to disclose.
Xianjun Dong, PhD (Brigham and Women's Hospital)	No disclosure on file
Kevin N. Sheth, MD, FAAN (Yale UniversityDivision of Neuro and Critical Care)	Dr. Sheth has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ceribell. Dr. Sheth has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Zoll. Dr. Sheth has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for NControl. Dr. Sheth has received stock or an ownership interest from Astrocyte. Dr. Sheth has received stock or an ownership interest from Alva. The institution of Dr. Sheth has received research support from Biogen. The institution of Dr. Sheth has received research support from Novartis. The institution of Dr. Sheth has received research support from Bard. The institution of Dr. Sheth has received research support from Hyperfine. Dr. Sheth has received intellectual property interests from a discovery or technology relating to health care.
Lauren H. Sansing, MD	Dr. Sansing has nothing to disclose.
Guido J. Falcone, MD (Yale School of Medicine)	The institution of Dr. Falcone has received research support from NIH. The institution of Dr. Falcone has received research support from AHA.

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