Grant Award Details

Use of Human iPSC-derived Endothelial Cells for Calcific Aortic Valve Disease Therapeutics
Grant Type: 
Grant Number: 
DISC2-09098
Project Objective: 

  • A small molecule therapeutic candidate(s) that arrests or delays calcific aortic valve disease and a genetic profile of potential responders.

Investigator: 
Name: 
Institution: 
Type: 
PI
Disease Focus: 
Heart Disease
Vascular Disease
Human Stem Cell Use: 
iPS Cell
Cell Line Generation: 
iPS Cell
Award Value: 
$2,400,048
Status: 
Closed

Progress Reports

Reporting Period: 
Year 2

Grant Application Details

Application Title: 
  • Use of Human iPSC-derived Endothelial Cells for Calcific Aortic Valve Disease Therapeutics
Public Abstract: 

Research Objective

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.

Impact

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.
Statement of Benefit to California: 

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.

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