GHRH agonists for the treatment of ischemic disorders

Inventors

Schally, Andrew V.Hare, Joshua M.Block, Norman L.GOMES, Samirah A.KANASHIRO-TAKEUCHI, Rosemeire M.

Assignees

University of MiamiUS Department of Veterans Affairs

Publication Number

US-9855312-B2

Publication Date

2018-01-02

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

This invention provides compositions of growth hormone releasing hormone (GHRH) agonist peptides and related methods for treating disorders such as ischemia and reperfusion injury. The disclosed methods include administering a therapeutically effective amount of at least one GHRH agonist peptide to subjects in need to treat reperfusion injury, promote vasculogenesis, and encourage differentiation of mesenchymal stem cells into endothelial cells.

The problem solved by this invention addresses the paradoxical dysfunction that occurs upon reperfusion of ischemic tissue, including endothelial cell dysfunction leading to vasoconstriction, acute immune response, and increased oxidative processes, which complicate recovery despite restoration of blood flow. Existing angiogenesis techniques such as gene therapy and use of growth factors have limitations. This invention leverages modified GHRH agonists with enhanced receptor binding, resistance to enzymatic degradation, and maintained physiological activity to directly target ischemic disorders and promote vascular repair and regeneration.

The compositions comprise novel synthetic peptide analogs of human GHRH (hGHRH 1-29 or 1-30) featuring multiple amino acid substitutions, including N-Me-Tyr or des-Amino-Tyr at position 1 to protect against N-terminal enzymatic degradation and agmatine or similar substitutions at the C-terminus to resist proteolysis. Modifications also include replacement of lysines with ornithine, substitution of glycine by aminobutyric acid, and alterations to enhance chemical stability. These GHRH agonist peptides demonstrate high binding affinity for GHRH receptors, increased in vivo potency for growth hormone release, and biological activity conducive to therapeutic benefit in ischemic and reperfusion injury contexts.

Claims Coverage

The patent includes one independent claim related to therapeutic methods using a specific GHRH agonist peptide.

Method of treating reperfusion injury with GHRH agonist peptide

A method comprising administering a therapeutically effective amount of at least one GHRH agonist peptide, specifically P-27409 [N-Me-Tyr1, D-Ala2, Orn12, Abu15, Orn21, Nle27, Asp28] hGHRH(1-29) NH—CH3, to a subject in need to treat reperfusion injury.

Reperfusion injury caused by ischemic disorder or hypoxia

The reperfusion injury addressed by the method is caused by an ischemic disorder or hypoxia.

Treatment of ischemic disorder during surgical procedures

The ischemic disorder can occur during surgical procedures such as heart surgery, organ transplantation, angioplasty, or stenting, and the method includes administering the GHRH agonist peptide in these contexts.

Treatment of various ischemic disorders

The method applies to ischemic disorders including cardiovascular disease, cardiomyopathy, myocardial stunning, peripheral vascular disease, tachycardia, ischemia-reperfusion, myocardial infarction, cardiac fibrosis, cardiac weakness, or combinations thereof.

Treatment of ischemic disorders due to other pathological conditions

Ischemic disorders due to acute renal failure, stroke, hypotension, embolism, thromboembolism, sickle cell disease, localized pressure to extremities, tumors, or combinations thereof are treated by administering the GHRH agonist peptide.

The claims cover therapeutic methods employing specific GHRH agonist peptides to treat reperfusion injury caused by a variety of ischemic disorders and related conditions, including those arising during surgical interventions or systemic diseases.

Stated Advantages

The GHRH agonist peptides exhibit higher binding affinity to GHRH receptors than native hGHRH.

The peptides resist enzymatic degradation in vivo, thus increasing stability and biological activity.

They stimulate growth hormone release more potently and for longer duration compared to reference compounds like JI-38.

The methods promote cardiac repair after myocardial infarction, reducing infarct size and improving cardiac function.

The peptides enhance differentiation of mesenchymal stem cells into endothelial cells and promote vasculogenesis.

Documented Applications

Treatment of reperfusion injury in subjects suffering ischemia or hypoxia.

Treatment of ischemic disorders including cardiovascular disease, cardiomyopathy, myocardial stunning, peripheral vascular disease, and others.

Therapeutic use during heart surgery, organ transplantation, angioplasty, and stenting to mitigate ischemic injury.

Promotion of vasculogenesis in mammals by administering GHRH agonist peptides.

Promotion of differentiation of mesenchymal stem cells into endothelial cells both in vitro and in vivo.

Therapeutic strategy to improve cardiac repair and function after myocardial injury in rat models.

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