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Develop natural compound emodin as a novel therapy for calcific aortic valve disease

Award Number: R41HL172481
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/17/2024
PERIOD OF PERFORMANCE END DATE: 09/16/2026

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Develop natural compound emodin as a novel therapy for calcific aortic valve disease - Summary: Calcific aortic valve disease (CAVD) is a progressive heart disease ranging from aortic valve sclerosis to aortic valve stenosis, characterized by severe calcification with impaired leaflet function. CAVD affects 25% of the population over 65 years of age and about 50% of those over 85 years old. Male sex is one of the major risk factors of CAVD. Currently, the standard-of-care treatment of CAVD is surgical valve replacement, but there are no drugs approved by the FDA for CAVD treatment, calling for urgent research and drug development efforts. There are no good animal models that develop age and sex appropriate CAVD and are ideal for research and drug development. Mouse models that are currently used to study CAVD also develop atherosclerosis. while atherosclerosis is a major risk factor of CAVD, the pathophysiology of atherosclerosis and CAVD are quite distinct. Aberrant transforming growth factor β (TGFβ) signaling plays a key role in the pathogenesis of CAVD. Our preliminary studies indicated that transgenic overexpression of a constitutively active form of TGFβ1 in valve interstitial cells (VIC) (via Tgfb1Tg;PostnCre) causes CAVD in both sexes, and older male transgenic mice (8-10 months of age) predominantly progress to severe form of CAVD. We developed a novel In vitro mouse VIC calcification assay for both male and female sex and found that natural compound emodin (1,3,8-trihydroxy-6- methylanthraquinone) significantly blocked the progression of VIC calcification in vitro. An preliminary in vivo study showed that systemic delivery of emodin for 8 weeks was able to attenuate and/or reverse the established aortic valve calcification in Tgfb1Tg mice. Emodin has been investigated as a potential therapy for various diseases, but there is not enough attention paid to its therapeutic potential in CAVD. AcePre LLC and its associated laboratories at the University of South Carolina have studied emodin for multiple years and accumulated an extensive dataset related to its pharmacokinetics, toxicity, and therapeutic efficacy in various disease models. In this STTR Phase 1 project, we aim to take the emodin therapy forward using our unique clinically relevant mouse models of CAVD. Our hypothesis is that emodin may block the development and progression of CAVD and even lead to a reversal of CAVD by tempering the aberrant TGFβ signaling. Two specific aims are proposed. SA1: Test the hypothesis that emodin blocks the development and progression of calcific aortic valve disease. SA2: Test the hypothesis that emodin treatment will reduce or reverse the preexisting CAVD. Upon completion of this STTR Phase 1 project, we will in a Phase II project: 1) use large animal models to find a dose range that can be extrapolated to humans and test the safety and efficacy of emodin for the treatment of CAVD in a GLP setting, and 2) carry out cGMP manufacturing of emodin for human studies. These studies will enable us to file an investigational new drug (IND) application to FDA. The development of this emodin-based therapy may reduce or eliminate the need for surgical AV replacement in patients with CAVD.


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	2024	ACEPRE, LLC	6439 GARNERS FERRY	COLUMBIA	SC	29209	RICHLAND	USA	Cardiovascular Diseases Research	001	1	8/11/2025	NEW	$0
2025	2024	ACEPRE, LLC	6439 GARNERS FERRY	COLUMBIA	SC	29209	RICHLAND	USA	Cardiovascular Diseases Research	000	1	10/12/2024	NEW	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $299,953 )
2024	2024	ACEPRE, LLC	6439 GARNERS FERRY	COLUMBIA	SC	29209	RICHLAND	USA	Cardiovascular Diseases Research	000	1	9/16/2024	NEW	$299,953
														Subtotal = $299,953

Grand Total All Awards = $299,953

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Develop natural compound emodin as a novel therapy for calcific aortic valve disease

Award Number: R41HL172481

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/17/2024

PERIOD OF PERFORMANCE END DATE: 09/16/2026

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