Our objective is to advance innovative cardiorenal protective peptide therapeutics for heart failure (HF) with a special focus on the post-acute HF period, which is a high-risk phase of HF for rehospitalization and increased mortality. Our therapeutic target is the natriuretic peptide/particulate guanylyl cyclase-A receptor/cGMP (NP/pGC-A/cGMP) and Angiotensin1-7/Mas (ANG1-7/Mas) receptor pathways. Both possess cardiorenal protective and anti-renin-angiotensin-aldosterone system (RAAS) properties. An overriding theme is that optimal HF therapeutics must be multivalent promoting the NP/cGMP system while opposing RAAS. This theme is underscored by our hypothesis of an intrarenal imbalance between the NP/pGC-A/cGMP and RAAS pathways in human post-acute HF. Our proposal builds on our expertise in developing innovative designer NPs. HL36634 supported the development of CD-NP (Cenderitide), a dual pGC-A/pGC-B activator, which received an IND and is in clinical trials for HF. Here we advance NPA7, our newest generation designer peptide, which may represent a truly superior therapeutic for HF. NPA7 is a first-in-class multivalent peptide with dual receptor activating actions. NPA7, unlike CD-NP or native NPs, co-targets the cardiorenal protective pGC-A and Mas receptors for which ANP/BNP and ANG1-7 are endogenous ligands respectively. We hypothesize that NPA7 amplifies the cardiorenal protective properties via these two complementary pathways. We also hypothesize that NPA7 will have synergistic actions which go beyond pGC-A or Mas receptor activation alone. Preliminary studies in experimental HF reveal cardiorenal activation of deleterious molecular pathways of inflammation, apoptosis, and fibrosis. We hypothesize that such pathway activation may, in part, be linked to excessive cardiorenal angiotensin II (ANG II) and a relative deficiency of NP/cGMP, especially in the kidney, leading to detrimental cardiorenal structural changes and dysfunction, which is also supported by preliminary studies in experimental HF. This imbalance we hypothesize characterizes human post-acute HF. Indeed, defining this imbalance is important especially in the kidney in the setting of human post-acute HF in which there is insufficient knowledge of intrarenal RAAS and NP/cGMP pathway activity, and could support the rationale for co-targeting of the NP/cGMP and RAAS pathways with NPA7. The impact of our application is high, addressing the need for new drugs for post-acute HF for which there are no FDA approved therapies. Completion of our aims will advance innovation in the area of multivalent receptor activation, and move NPA7 to the IND ready level for clinical trials in post-acute HF.
Our Specific Aims are as follows:
Aim 1 : Determine pGC-A and Mas receptor binding of NPA7 in HEK293 cells selectively overexpressing human pGC- A or Mas receptors together with defining cardiorenal protective properties of NPA7 in human renal tubular cells, cardiomyocytes and renal and myocardial fibroblasts.
Aim 2 : Determine the cardiorenal protective properties and RAAS inhibiting actions of chronic NPA7 therapy in a large animal model of HF, which mimics post-acute HF.
Aim 3 : Determine urinary and circulating components of the NP/cGMP system and RAAS in human post-acute HF with a special focus on an intrarenal NP/cGMP and RAAS imbalance.

Public Health Relevance

There is a huge unmet need for the development of new and effective drugs for heart failure with a special focus on that period after a patient is discharged from the hospital for HF. We propose to advance the development of a novel therapeutic designer peptide (NPA7) engineered by the applicants based upon the natriuretic peptide and cGMP system and the angiotensin 1-7/Mas receptor pathway, which goes beyond the properties of the native natriuretic peptides as NPA7 activates two complementary cardiorenal protective pathways. This highly innovative peptide will be tested in a large animal model of HF, which mimics post-acute HF. In addition, we will elucidate for the first time a potential imbalance between the intrarenal renin- angiotensin-aldosterone and natriuretic peptide/cGMP pathways in human post-acute HF providing a target for our innovative cardiorenal protective peptide.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
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Sopko, George
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Mayo Clinic, Rochester
United States
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Kawakami, Rika; Lee, Candace Y W; Scott, Christopher et al. (2018) A Human Study to Evaluate Safety, Tolerability, and Cyclic GMP Activating Properties of Cenderitide in Subjects With Stable Chronic Heart Failure. Clin Pharmacol Ther 104:546-552
Ichiki, Tomoko; Dzhoyashvili, Nina; Burnett Jr, John C (2018) Natriuretic peptide based therapeutics for heart failure: Cenderitide: A novel first-in-class designer natriuretic peptide. Int J Cardiol :
Chen, Yang; Burnett, John C (2018) Particulate Guanylyl Cyclase A/cGMP Signaling Pathway in the Kidney: Physiologic and Therapeutic Indications. Int J Mol Sci 19:
Lee, Candace Y W; Huntley, Brenda K; McCormick, Daniel J et al. (2016) Cenderitide: structural requirements for the creation of a novel dual particulate guanylyl cyclase receptor agonist with renal-enhancing in vivo and ex vivo actions. Eur Heart J Cardiovasc Pharmacother 2:98-105
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Ichiki, Tomoko; Huntley, Brenda K; Sangaralingham, S Jeson et al. (2015) Pro-Atrial Natriuretic Peptide: A Novel Guanylyl Cyclase-A Receptor Activator That Goes Beyond Atrial and B-Type Natriuretic Peptides. JACC Heart Fail 3:715-23
Zakeri, Rosita; Burnett Jr, John C; Sangaralingham, S Jeson (2015) Urinary C-type natriuretic peptide: an emerging biomarker for heart failure and renal remodeling. Clin Chim Acta 443:108-13
Buglioni, Alessia; Burnett Jr, John C (2015) Pathophysiology and the cardiorenal connection in heart failure. Circulating hormones: biomarkers or mediators. Clin Chim Acta 443:3-8
Miller, Wayne L; Borgeson, Daniel D; Grantham, J Aaron et al. (2015) Dietary sodium modulation of aldosterone activation and renal function during the progression of experimental heart failure. Eur J Heart Fail 17:144-50

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