Small molecule therapeutic for calcific aortic valve disease - PROJECT SUMMARY Aortic valve stenosis is the major cause of valve disease in the Western world, and the third leading cause of adult heart disease. It is a progressive disorder associated with calcification that worsens with aging, thus is rising in prevalence as the worldwide population ages. There is an unmet need to develop medical therapeutics for this condition, as the only treatment for calcific aortic valve disease (CAVD) involves valve replacement. A major risk factor for calcific aortic valve disease (CAVD) is bicuspid aortic valve (BAV), which is present in 1–2% of the population, and involves formation of a two, rather than three, leaflet valve. ~35% of individuals with BAV will develop CAVD with age, but some with BAV display leaflet thickening even in childhood. We have previously reported that loss-of-function mutations in the NOTCH1 gene cause congenital bicuspid aortic valve (BAV) and early-onset CAVD. Patient-specific iPSCs and primary aortic valve cells from CAVD patients without NOTCH1 mutations revealed that abnormal cell fate conversion of valve cells into osteoblast-like cells is the underlying pathogenesis of CAVD. Using a gene network-based small molecule library screen and a machine learning algorithm, we found the compound XCT790 broadly corrected gene dysregulation in NOTCH1 haploinsufficient human iPSC-derived endothelial cells. We postulated XCT790 may function to modulate the cell fate conversion event regardless of the inciting genetic cause as we did not screen for a NOTCH1 agonist; indeed, in primary aortic valve endothelial cells from explanted patient valves without evidence of NOTCH1 mutations, the dysregulated gene network was corrected in the vast majority of patient cells. In a mouse CAVD model, XCT790, annotated to inhibit estrogen-related receptor-a (ERRa), reduced valvular thickening, stenosis and calcification in vivo, positing this compound as a strong candidate for therapeutic intervention in CAVD patients. A second ERRa inhibitor, Compound 29, also corrected gene networks and appears to arrest established disease in mice. Here we will test the hypothesis that XCT790 prevents the progression of CAVD by targeting ERRα, and that XCT790 or an oral ERRa inhibitor, Compound 29, has favorable pharmacokinetics and toxicity properties for further drug development. We propose to achieve this by pursuing the following Aims: 1) Identification of the molecular target associated with therapeutic activity of XCT790/Compound 29 for CAVD; 2) Determine minimal dosing and optimal route of administration for XCT790 and Compound 29 for treating two independent models of CAVD; and 3) Evaluate pharmacokinetics and potential toxicities of XCT790 and Compound 29 in vivo. These studies will test the therapeutic potential of XCT790 and Compound 29, and establish the groundwork for clinical translation of these drugs to treat a disease that represents an enormous unmet medical need, is characterized by high mortality and morbidity, and for which the main current remedy is invasive surgery.
