Our objective is to advance innovative protein therapeutics for acute myocardial infarction (AMI) in which we target both the heart and kidney with the goal of preventing post AMI cardiorenal remodeling and heart failure (HF). Our approach is built on the concept that a novel Mayo engineered guanylyl cyclase (GC) activator possesses pleuripotent cardiorenal protective properties, which preserves myocardial and renal structure and function following AMI. Our application also proposes a novel strategy for chronic peptide delivery, which is key in optimizing inhibition of post-AMI cardiorenal impairment by protein therapeutics. Studies are proposed in both experimental and human AMI. Our proposal represents an advanced therapeutic strategy designed to go beyond native natriuretic peptides (NPs) with the use of the first dual GC receptor chimeric NP (GC-B>GC-A affinity) that combines key amino acids (AA) from CNP, a GC-B agonist, and DNP, a GC-A agonist. CD-NP is now in clinical trials for acute HF following recent completion of a first in human study in normal volunteers. CD-NP was designed by the applicants to exploit characteristics of CNP so that CD-NP would be less hypotensive than BNP and possess renal enhancing, cardiac preload reducing and RAAS suppressing actions by integrating the C-terminus of DNP. Our drug development strategy recognizes the pleuripotent properties of the endogenous NPs, which are mediated by particulate GC receptors, which include GC-A to which ANP and BNP bind and GC-B to which CNP binds. These beneficial properties include natriuresis, vasorelaxation, inhibition of myocyte hypertrophy and apoptosis, suppression of fibrosis, positive lusitropism, angiogenesis and renin-angiotensin-aldosterone (RAAS) suppression. Importantly, our application in experimental and human post AMI remodeling goes beyond the heart and also focuses on the kidney recognizing the increasingly prognostic importance of post AMI renal injury which increases future risk for HF.
Specific Aim 1 : Determine cardiorenal protective mechanisms of chronic subcutaneous infusion of CD-NP in preserving cardiorenal function and structure post-experimental AMI. Hypothesis: CD-NP will suppress cardiorenal fibrosis, reduce myocyte apoptosis, preserve coronary microvascular volume, maintain podocytes integrity and inhibit aldosterone following AMI.
Specific Aim 2 : Define in a proof of concept human study the safety and cardiorenal actions of CD-NP in human AMI. Hypothesis: CD-NP will be safe, activate plasma and urinary cGMP, suppress aldosterone and one month following administration, will be associated with improved cardiorenal function and structure. Thus, the impact of our proposal is high. Specifically, our approach advances novel drug development and delivery, with the goal of preventing HF by suppressing post AMI structural and functional impairment of the heart. Further, our high impact post AMI therapeutic strategy also targets renal protection. Finally, we take a highly translational approach by combining studies of both experimental and human AMI.

Public Health Relevance

There is a huge unmet need for new, safe and effective drugs to protect the heart and kidney after myocardial infarction so as to reduce the burden of heart failure. We have engineered a highly innovative designer peptide to preserve cardiorenal structure and function following myocardial infarction and now propose to advance this strategy in both experimental and human myocardial infarction including its chronic delivery by subcutaneous delivery.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL083231-06
Application #
8428594
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Sopko, George
Project Start
2005-12-01
Project End
2016-11-30
Budget Start
2012-12-01
Budget End
2013-11-30
Support Year
6
Fiscal Year
2013
Total Cost
$513,971
Indirect Cost
$180,039
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
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Ichiki, Tomoko; Schirger, John A; Huntley, Brenda K et al. (2014) Cardiac fibrosis in end-stage human heart failure and the cardiac natriuretic peptide guanylyl cyclase system: regulation and therapeutic implications. J Mol Cell Cardiol 75:199-205
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