GHRH agonists for the treatment of ischemic disorders
Inventors
Schally, Andrew • Hare, Joshua M. • Block, Norman • Gomes, Samirah • KANASHIRO-TAKEUCHI, Rosemeire M.
Assignees
University of Miami • US Department of Veterans Affairs
Publication Number
US-10555987-B2
Publication Date
2020-02-11
Expiration Date
2033-12-23
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Abstract
Disclosed herein are compositions of GHRH agonists and peptides, and methods to treat disorders, such as ischemia and reperfusion injury. In one embodiment, a method of treating a reperfusion injury in a subject in need may involve administering a therapeutically effective amount of at least one GHRH agonist peptide to the subject. In additional embodiment, a method of promoting vasculogenesis in a mammal may involve administering a therapeutically effective amount of at least one GHRH agonist peptide to the subject. In a further embodiment, a method of promoting differentiation of mesenchymal stem cells into endothelial cells may involve contacting mesenchymal stem cells with at least one GHRH agonist peptide.
Core Innovation
The invention provides novel compositions of growth hormone releasing hormone (GHRH) agonists and peptides, along with methods for treating disorders such as ischemia and reperfusion injury. The GHRH agonist peptides are designed to bind with high affinity to the GHRH receptor and to promote therapeutic effects including vasculogenesis and differentiation of mesenchymal stem cells into endothelial cells, both in vitro and in vivo.
The problem addressed by the invention involves the insufficient treatment options for ischemic necrosis or infarction caused by deprivation of blood and oxygen to tissues. Conventional restoration of blood flow (reperfusion) can paradoxically cause endothelial dysfunction and inflammatory responses that impair healing. Existing therapies such as gene therapy and use of growth factors have limited efficacy. Prior GHRH peptides do not effectively resist enzymatic degradation or provide optimal receptor affinity, limiting their therapeutic potential.
The invention solves these problems by providing synthetic peptide analogs of human GHRH (1-29 or 1-30 amino acids) with multiple amino acid substitutions that increase their receptor binding affinities and resistance to enzymatic degradation, thereby enhancing their biological activity and stability. Specifically, modifications include N-methyl-tyrosine or des-amino-tyrosine at position 1 to protect the N-terminus, agmatine or amide modifications at the C-terminus to protect from C-terminal degradation, and replacements of susceptible amino acids such as lysine with ornithine. These peptide agonists effectively promote vasculogenesis, differentiation of stem cells to endothelial cells, and improve cardiac repair after ischemic injury.
Claims Coverage
The patent contains one independent claim focusing on a method of promoting vasculogenesis using a specific GHRH agonist peptide.
Use of a specific GHRH agonist peptide for promoting vasculogenesis
Administering a therapeutically effective amount of the GHRH agonist peptide P-27409 [N-Me-Tyr1, D-Ala2, Orn12, Abu15, Orn21, Nle27, Asp28]hGHRH(1-29)NH—CH3 or a pharmaceutically acceptable salt thereof to a subject to promote vasculogenesis.
The independent claim covers a method for promoting vasculogenesis through administration of a specific chemically modified GHRH agonist peptide with enhanced receptor binding and stability.
Stated Advantages
The GHRH agonist peptides have increased potency and stability compared to native GHRH and prior analogs due to resistance to enzymatic degradation.
The peptides demonstrate enhanced growth hormone releasing activity in vivo and higher binding affinity to GHRH receptors in vitro.
Treatment with these agonists results in improved cardiac repair after myocardial infarction, including reduced infarct size, increased mitotic activity of cardiomyocytes, increased number of c-kit+ cells, enhanced vasculogenesis and improved cardiac function.
The peptides promote differentiation of mesenchymal stem cells into endothelial cells and rescue impaired angiogenic potential in deficient stem cells.
The agonists show prolonged endocrine potency and are effective when administered by multiple routes including subcutaneous and intravenous injections.
Documented Applications
Treatment of reperfusion injury caused by ischemia or hypoxia in subjects in need thereof.
Treatment of ischemic disorders including cardiovascular disease, cardiomyopathy, myocardial stunning, peripheral vascular disease, intermittent claudication, tachycardia, ischemia-reperfusion injury, myocardial infarction, cardiac fibrosis, cardiac weakness, acute renal failure, stroke, hypotension, embolism, thromboembolism, sickle cell disease, localized pressure to extremities and tumors.
Promotion of vasculogenesis in mammals and experimental animals.
Promotion of differentiation of mesenchymal stem cells into endothelial cells both in vitro and in vivo.
Use in cardiac repair and functional improvement following myocardial infarction in rat models.
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