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.

Grant Number: 1R41HL172481-01
NIH Institute/Center: NIH
Principal Investigator: Mohamad Azhar