Ac5 inhibitor treatment for heart failure

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Project Title: Ac5 inhibitor treatment for heart failure
Project Number: 1P20HL101420-01
Project web address: Follow on NIH
Organization: Univ Of Med/Dent Of Nj-Nj Medical School, United States, New Jersey, NEWARK
Principal Investigators (PI): Vatner Stephen F, US
 
Project Description:
Congestive heart failure (HF) in the U.S is the leading cause of death, and the major cause of HF is myocardial ischemic disease. Therefore, improvement of therapy post myocardial infarction (Ml) is extremely important, and the development of a new class of medicine that prevents the progression of HF would have a large market opportunity, representing a significant clinical advance. Additionally, most of these patients have elevated blood lipids and many have impaired glucose metabolism and are either diabetic or pre-diabetic. Therefore, a HF drug which can exert a favorable effect on diabetes control will have a unique niche in the HF market. The goal of this grant proposal is to demonstrate the efficacy of a new class of HF drugs, with a mechanism of inhibition of type 5 adenylyl cyclase (ACS), to improve the adverse effects of remodeling following chronic Ml and to simultaneously improve disorders of glucose metabolism,. This proposal is based on our prior work in a mouse model with disruption of the ACS gene, i.e., ACS knockout mice (ACS KO), and based on the utilization of a specific pharmacological ACS inhibitor. ACS KO mice have prolonged lifespan and are protected from the cardiomyopathy of aging. They are also protected against the development of HF induced by either chronic pressure overload, or by excessive sympathetic stimulation. Another unique feature of the ACS KO mouse model is its ability to increase coronary reserve, which should be particularly useful in preventing the development of HF. Importantly for this proposal these mice eat more than wild type, but weigh less, which points to a favorable metabolic profile, confirmed by our preliminary data using a specific pharmacological ACS inhibitor. In our preliminary screening for ACS inhibitors, adenine 9-?-D-arabinofuranoside (AraAde, also known as Vidarabine or Vira-A(r)), which was used in the clinic for a different indication, i.e., treating viral infections, showed potent and selective inhibition of ACS. Furthermore, our preliminary data demonstrate that the pharmacological AC 5 inhibitor protects against HF following chronic Ml and also protects against development of hyperglycemia induced by a high-fat diet in mice, suggesting that inhibition of ACS improves glucose metabolism in addition to its salutary effects in protecting against HF. Accordingly, in this preclinical study, we will examine the effects of AraAde on post-MI HF with or without impaired glucose metabolism. In addition we will examine the efficacy of this drug in the best pre-clinical model for HF, the chronically instrumented, conscious monkey post-MI. RELEVANCE (See instructions): Almost 5.5 million patients are diagnosed with congestive heart failure in the U.S and the major cause of HF is myocardial ischemic disease. However, no effective therapy has been established to treat congestive HF. The current investigation is aimed at generating a new class of medicine that will prevent progression of HF. Due to the large number of patients with this condition, this may have a significant impact on public health.
 
Project Terms:
adenine adenylate cyclase adenylyl cyclase type v adverse effects aging applications grants arasena-a base blood lipid cardiomyopathies cause of death chronic clinic clinical congestive heart failure conscious coronary data development diabetes control diabetic diagnosis diet disease drug efficacy eating effective therapy fatty acid glycerol esters genes glucose metabolism glucose metabolism disorders goals heart failure hyperglycemia improved inhibitor/antagonist instruction instrument investigation knockout mice longevity marketing medicine metabolic monkeys mouse model mus myocardial myocardial infarction patients pharmaceutical preparations pre-clinical model preclinical study pressure prevent public health medicine (field) screening procedure vidarabine virus diseases work nutrition prevention cardiovascular heart disease
Project Title: Ac5 inhibitor treatment for heart failure
Project Number: 1P20HL101420-01
Project web address: Follow on NIH
Organization: Univ Of Med/Dent Of Nj-Nj Medical School, United States, New Jersey, NEWARK
Principal Investigators (PI): Vatner Stephen F, US
 
Project Categories:
Natural Sciences
 
Other Information:
Fiscal Year: 2010
Project Start Date: 1 April 2010
Project End Date: 31 March 2012
Project program: Exploratory Grants
 
Project Funding Information:
Funding Mechanism: Research Centers
Year Funding Organization Total Funding, $
2010 NIH - National Heart, Lung, And Blood Institute $779,111
Project Title: Ac5 inhibitor treatment for heart failure
Project Number: 1P20HL101420-01
Project web address: Follow on NIH
Organization: Univ Of Med/Dent Of Nj-Nj Medical School, United States, New Jersey, NEWARK
Principal Investigators (PI): Vatner Stephen F, US
 
Title FY Funding
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Project Title: Ac5 inhibitor treatment for heart failure
Project Number: 1P20HL101420-01
Project web address: Follow on NIH
Organization: Univ Of Med/Dent Of Nj-Nj Medical School, United States, New Jersey, NEWARK
Principal Investigators (PI): Vatner Stephen F, US
 
Project Title Organization FY Funding
Ac5 Inhibitor Treatment For Heart FailureUniv Of Med/Dent Of Nj-Nj Medical School2011$779,111
Ac5 Inhibitor Treatment For Heart FailureUniv Of Med/Dent Of Nj-Nj Medical School2010$779,111
Project Title: Ac5 inhibitor treatment for heart failure
Project Number: 1P20HL101420-01
Project web address: Follow on NIH
Organization: Univ Of Med/Dent Of Nj-Nj Medical School, United States, New Jersey, NEWARK
Principal Investigators (PI): Vatner Stephen F, US
 
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