Grant Award Details
A small molecule therapeutic candidate(s) that arrests or delays calcific aortic valve disease and a genetic profile of potential responders.
Grant Application Details
- Use of Human iPSC-derived Endothelial Cells for Calcific Aortic Valve Disease Therapeutics
To develop drugs to treat Calcific Aortic Valve Disease (CAVD), the third leading cause of adult heart disease, by screening a stem cell-based platform based on CAVD patient-derived stem cells.
CAVD represents a major unmet medical need, with no treatments other than valve replacement. We will identify drugs, already proven to be safe, that normalize gene dysregulation and prevent CAVD.
Major Proposed Activities
- Generate iPSCs from 100 subjects with early onset CAVD and BAV.
- Perform genetic analyses of the 100 subjects for enrichment of variants in N1-related gene networks and osteogenic networks.
- Derive endothelial cells from CAVD iPSC lines, and study their gene expression under biophysical conditions related to valve calcification.
- Screen nine drugs validated in N1+/– iPSC-ECs for their effects on correcting gene network dysfunction in sporadic CAVD patient-derived iPSC-ECs.
- Determine efficacy of nine drugs validated in N1+/– iPSC-ECs in preventing CAVD in a mouse model.
- Initiate studies of optimal dosing and timing of potential therapeutic compound, which will be determined by best efficacy in Activity 5.
This research will benefit California by developing drugs to treat Calcific Aortic Valve Disease (CAVD), a major unmet medical need that imposes a serious economic burden. The only clinical option is valve replacement, with 100,000 patients receiving transplants per year in the US. To address this, we will use a stem cell-based platform based on CAVD patient-derived stem cells to test drugs, already proven to be safe, that normalize gene dysregulation and prevent CAVD.