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Aortic Valve Disease: Mechanisms and Therapeutic Approaches

Award Number: R01HL150100
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/10/2020
PERIOD OF PERFORMANCE END DATE: 01/31/2025

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Aortic Valve Disease: Mechanisms and Therapeutic Approaches - 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 that worsens with age. Thickening of the aortic valve is followed by calcification that results in further stenosis that ultimately necessitates surgical 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-valve leaflet. ~35% of individuals with BAV will develop CAVD with age, but some with BAV have thickening even in childhood, requiring intervention. There are no medical treatments available for CAVD patients, and the only clinical option is surgical valve replacement. We reported that heterozygous nonsense mutations in the NOTCH1 (N1) transcription factor cause congenital biscuspid aortic valve (BAV) and severe CAVD and evidence suggests N1 is haploinsufficient in valve endothelial cells (ECs). Induced pluripotent stem cell (iPSC)-derived ECs from several patients with CAVD and N1 haploinsufficiency showed increased expression of pro-osteogenic and inflammatory signaling. Network analysis revealed key nodes that were responsible for much of the gene dysregulation. A chemical screen for the ability to restore expression of 120 dysregulated genes by targeted RNA-sequencing revealed several drugs that restored the network close to the N1+/+ state in human iPSC-ECs, with one, XCT790, showing efficacy in vivo for aortic valve thickening, calcification and stenosis in a mouse model. XCT790 is annotated to function as an inhibitor of estrogen-related receptor alpha (ERRα). We now propose to test the hypotheses that XCT790 prevents aortic valve disease by inhibiting ERRα activity, can treat established disease, and can function in a subset of CAVD patient cells without N1 mutations. The aims are 1) to determine the mechanism of action by which XCT790 corrects disease-associated gene expression and prevents aortic valve disease; 2) to determine if XCT790 can treat established CAVD or prevent neonatal valve stenosis; and 3) to determine if gene dysregulation in primary aortic valve endothelial cells from sporadic CAVD patients with or without genetic variants in NOTCH1 pathway genes is responsive to XCT790. These studies will advance a potential therapeutic to treat a disease that represents an enormous unmet medical need, is characterized by high mortality and morbidity, and for which the only current remedy is a highly invasive surgery.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2023	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Cardiovascular Diseases Research	000	4	6/5/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $679,124 )
2023	2023	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Cardiovascular Diseases Research	000	4	1/6/2023	NON-COMPETING CONTINUATION	$611,213
2023	2023	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Cardiovascular Diseases Research	001	4	3/10/2023	NON-COMPETING CONTINUATION	$67,911
														Subtotal = $679,124

Issue Date FY: 2022 ( Subtotal = $679,124 )
2022	2022	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Cardiovascular Diseases Research	000	3	1/10/2022	NON-COMPETING CONTINUATION	$611,212
2022	2022	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Cardiovascular Diseases Research	001	3	5/31/2022	NON-COMPETING CONTINUATION	$67,912
														Subtotal = $679,124

Issue Date FY: 2021 ( Subtotal = $679,124 )
2021	2021	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Cardiovascular Diseases Research	001	2	5/26/2021	NON-COMPETING CONTINUATION	$67,912
2021	2021	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Cardiovascular Diseases Research	000	2	1/29/2021	NON-COMPETING CONTINUATION	$611,212
														Subtotal = $679,124

Issue Date FY: 2020 ( Subtotal = $679,124 )
2020	2020	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Cardiovascular Diseases Research	000	1	2/10/2020	NEW	$679,124
														Subtotal = $679,124

Grand Total All Awards = $2,716,496

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Aortic Valve Disease: Mechanisms and Therapeutic Approaches

Award Number: R01HL150100

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 02/10/2020

PERIOD OF PERFORMANCE END DATE: 01/31/2025

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