Research team
Expertise
My research focuses on identifying drugs for rare aortic pathologies such as Marfan syndrome, Loeys-Dietz syndrome, and non-syndromic thoracic aortic aneurysms. This involves combining transcriptomics data from mouse models with large-scale human genetics to identify potential therapeutic targets. Through gene expression analysis in multiple genetic mouse models, common disease mechanisms are identified that are present across the entire spectrum of aortic pathology, from syndromic to non-syndromic forms. These computationally identified targets are subsequently genetically validated in human populations to confirm their causal role. Finally, existing drugs are experimentally tested in iPSC-derived vascular smooth muscle cells from patients with different genetic backgrounds. This integrated approach aims to lead to repurposed treatments that are broadly applicable for patients with aortic pathology.
Repurposing kinase inhibitors for TAA: from patient-derived VSMCs to Marfan mice.
Abstract
Heritable aortopathies, including Marfan and Loeys-Dietz syndromes, predispose to thoracic aortic aneurysm (TAA), which can progress to aortic dissection and rupture, complications associated with substantial morbidity and mortality. Despite identification of more than 30 TAA-causing genes, current medical therapy is limited to β-blockers and angiotensin receptor blockers, which only modestly slow aneurysm progression. To identify shared therapeutic vulnerabilities, I analyzed transcriptomic data from four genetically distinct TAA mouse models (Fbn1C1041G/+, Smad3−/−, Tgfbr2G357W/+, Ipo8−/−) using CARNIVAL causal network reconstruction. I identified five druggable kinases with consistently increased activation across all four models. This convergence indicates that genetically diverse forms of TAA share downstream signaling dependencies amenable to therapeutic intervention. This project will validate eight inhibitors targeting these kinases, plus EXP3174 (active losartan metabolite) as comparator, at four concentrations in patient-derived iPSC-VSMCs from three TAA genotypes (FBN1, SMAD3, IPO8) and isogenic controls. Drug-seq will assess disease-signature reversal; Western blot will confirm target engagement; and lead compounds will advance to in vivo testing in Fbn1C1041G/+ mice. This represents the first cross-genotype evaluation of shared TAA therapeutic targets, closing the translational loop from computational discovery to preclinical validation and accelerating development of disease-modifying therapies for patients with Marfan syndrome and related aortopathies.Researcher(s)
- Promoter: Steyaert Wouter
Research team(s)
Funding
- PRIVE - non profit
Project type(s)
- Research Project
Validating Therapeutic Targets for Thoracic Aortic Aneurysm: High-Throughput Drug Screening in Patient-Derived Cells.
Abstract
Background: Thoracic aortic aneurysm (TAA) is a life-threatening, often asymptomatic progressive dilatation of the aorta. Dissection or rupture results in death for up to 50% of patients before hospital admission. Beta-blockers and angiotensin II receptor blockers only modestly attenuate growth; disease-modifying therapies are lacking. Rationale: Previous studies validated only individual compounds in single genetic models. Through bulk RNA-seq analysis of four genetically diverse TAA mouse models (including Marfan and Loeys-Dietz syndrome), we identified convergent activation of a limited number of kinases that drive inflammatory and stress-activated signaling pathways. Based on these findings, we selected five clinically tested, oral kinase inhibitors that enable rapid translational validation. Approach: Drug-seq transcriptomics will be used to simultaneously test these five kinase inhibitors plus the standard-of-care ARB losartan in iPSC-derived vascular smooth muscle cells from three genetically distinct TAA patients and their isogenic CRISPR-corrected controls. The experimental design comprises (6 drugs × 3 doses + vehicle) × 6 cell lines × 3 replicates = 342 conditions. We will quantify reversal of disease-specific expression signatures and modulation of relevant signaling pathways, including dose-response and genotype specificity. Western blot validation confirms kinase inhibition at the protein level. Expected outcome: This project identifies which kinase inhibitors effectively reverse TAA signatures in human cells and yields patient cell-validated drugs with optimal dosing regimens for immediate in vivo validation. This systematic multi-compound, multi-genotype approach (the first in TAA research) additionally establishes a generalizable framework for transcriptomics-guided drug development in genetic disorders.Researcher(s)
- Promoter: Steyaert Wouter
Research team(s)
Funding
- BOF
Project type(s)
- Research Project