SBIR-STTR Award

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 ß (TGFß) signaling plays a key role in the pathogenesis of CAVD. Our preliminary studies indicated that transgenic overexpression of a constitutively active form of TGFß1 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 TGFß 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.

Public Health Relevance Statement:
Narrative Calcific aortic valve disease (CAVD), the third leading cause of heart disease, has higher incidence in men than women and that aortic valve calcification may be affected by congenitally bicuspid aortic valve disease and levels of cytokine transforming growth factor beta1. Unfortunately, there is no medical treatment, and without surgery, calcific aortic valve disease leads to death. In this project we will use unique preclinical mouse model of CAVD to determine mechanisms involved in the pathogenesis of CAVD, and test if the natural compound emodin can attenuate and/or reverse aortic valve calcification. Terms: <1, 3, 8-trihydroxy-6-methyl-9, 10-anthracenedione; 21+ years old; 3-Methyl-1, 6, 8-trihydroxy-antraquinone; 65 and older; 65 or older; 65 years of age and older; 65 years of age or more; 65 years of age or older; 65+ years; 65+ years old; 85+ years old; > 65 years; Adult; Adult Human; Adventitial Cell; Affect; Age; Age Months; Age Years; Aged 65 and Over; Animal Model; Animal Models and Related Studies; Aorta; Aortic Stenosis; Aortic Valve Stenosis; Aortic valvular disorders; Archin; Assay; Atherosclerosis; Atherosclerotic Cardiovascular Disease; Attention; Attenuated; Autoregulation; Binding; Bioassay; Biochemical; Biological Assay; Bone Marrow; Bone Marrow Reticuloendothelial System; Bone-Derived Transforming Growth Factor; Calcified; Cardiac Diseases; Cardiac Disorders; Cell Body; Cell Communication and Signaling; Cell Lineage; Cell Signaling; Cells; Cessation of life; Cyclic GMP; Data Set; Death; Deposit; Deposition; Development; Development and Research; Disease; Disorder; Dose; Drug Kinetics; Drugs; Dysfunction; Echography; Echotomography; Emodin; FDA approved; Female; Fibroblasts; Frangula Emodin; Frangulic Acid; Functional disorder; Guanosine Cyclic Monophosphate; Heart; Heart Diseases; Heart failure; Histology; Homeostasis; Human; Hypertension; Impairment; In Vitro; Incidence; Intracellular Communication and Signaling; Investigational New Drug Application; Laboratories; Lead; Left Ventricular Function; Maps; Medical; Medical Ultrasound; Medication; Membrane; Mice; Mice Mammals; Milk Growth Factor; Minerals; Modern Man; Molecular Interaction; Murine; Mus; Myocarditis; Natural Compound; Operative Procedures; Operative Surgical Procedures; Osteoblasts; Pathogenesis; Pathologic Constriction; Pathological Constriction; Patients; Pb element; Pericapillary Cell; Pericytes; Perivascular Cell; Pharmaceutical Preparations; Pharmacokinetics; Phase; Physiologic; Physiological; Physiological Homeostasis; Physiopathology; Platelet Transforming Growth Factor; Play; Population; R & D; R&D; Research Specimen; Rheum Emodin; Risk Factors; Rouget Cells; STTR; Sclerosis; Signal Transduction; Signal Transduction Systems; Signaling; Site; Small Business Technology Transfer Research; South Carolina; Specimen; Stenosis; Surgical; Surgical Interventions; Surgical Procedure; Surgical Valves; TGF B; TGF-Beta 1; TGF-Beta1; TGF-beta; TGF-ß; TGFB; TGFB1; TGFB1 gene; TGFbeta; TGFß; Testing; Therapeutic; Toxic effect; Toxicities; Transforming Growth Factor Beta 1; Transforming Growth Factor beta; Transforming Growth Factor-Beta Family Gene; Transgenic Mice; Transgenic Organisms; Treatment Efficacy; Ultrasonic Imaging; Ultrasonogram; Ultrasonography; Ultrasound Diagnosis; Ultrasound Medical Imaging; Ultrasound Test; Universities; Vascular Hypertensive Disease; Vascular Hypertensive Disorder; Woman; X-ray microtomography; Xray microtomography; above age 65; adulthood; after age 65; age 65 and greater; age 65 and older; age 65 or older; age 85 and greater; age 85 and older; age > 65; age of 65 years onward; aged 65 and greater; aged 65+; aged 85 and greater; aged 85 and older; aged ≥65; ages; aortic valve; aortic valve defect; aortic valve disease; aortic valve disorder; aortic valve replacement; aortic valvular disease; atheromatosis; atherosclerotic disease; atherosclerotic vascular disease; attenuate; attenuates; bicuspid aortic valve; biological signal transduction; cGMP; calcification; cardiac failure; cardiac inflammation; clinical relevance; clinically relevant; confocal imaging; cytokine; developmental; diagnostic ultrasound; disease model; disorder model; drug development; drug/agent; elderly patient; heart disorder; heavy metal Pb; heavy metal lead; high blood pressure; human old age (65+); human very old age (85+); hyperpiesia; hyperpiesis; hypertensive disease; hypertensive disorder; improved; in vivo; in vivo monitoring; insight; interstitial cell; intervention efficacy; male; manufacture; membrane structure; men; micro CT; micro computed tomography; microCT; microtomography; model of animal; mouse model; murine model; naturally occurring compound; new drug treatments; new drugs; new pharmacological therapeutic; new therapeutics; new therapy; next generation therapeutics; novel; novel drug treatments; novel drugs; novel pharmaco-therapeutic; novel pharmacological therapeutic; novel therapeutics; novel therapy; old age; older patient; over 65 years; overexpress; overexpression; pathophysiology; pre-clinical; preclinical; research and development; response; restraint; safety testing; sex; sonogram; sonography; sound measurement; standard of care; surgery; therapeutic efficacy; therapy efficacy; transforming growth factor beta1; transgenic; ultrasound imaging; ultrasound scanning; valve replacement; very old age; ≥65 years