Cardioprotective effects of GHRH agonists
Inventors
Schally, Andrew V. • Block, Norman L • Hare, Joshua • Kanashiro Takeuchi, Rosemeire Miyuki
Assignees
University of Miami • US Department of Veterans Affairs
Publication Number
US-8507433-B1
Publication Date
2013-08-13
Expiration Date
2030-10-28
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
Whether the growth hormone (GH)/Insulin-like growth factor 1(IGF-I) axis exerts cardioprotective effects remains controversial; and the underlying mechanism(s) for such actions are unclear. Here we tested the hypothesis that growth-hormone releasing hormone (GHRH) directly activates cellular reparative mechanisms within the injured heart, in a GH/IGF-I independent fashion. Following experimental myocardial infarction (MI), rats were randomly assigned to receive, during a 4 week period, either placebo (n=14), rat recombinant GH (rrGH, n=8) or JI-38 (n=8; 50 μg/Kg/day), a potent GHRH-agonist. JI-38 did not elevate serum levels of GH or IGF-I, but markedly attenuated the degree of cardiac functional decline and remodeling after injury. In contrast, GH administration markedly elevated body weight, heart weight, circulating GH and IGF-I, but did not offset the decline in cardiac structure and function. Whereas, both JI-38 and GH augmented levels of cardiac precursor cell proliferation, only JI-38 increased anti-apoptotic gene expression. The receptor for GHRH was detectable on myocytes supporting direct activation of cardiac signal transduction. Collectively, these findings demonstrate that within the heart GHRH-agonists can activate cardiac repair following MI, suggesting the existence of a potential signaling pathway based on GHRH in the heart. The phenotypic profile of the response to a potent GHRH agonist has therapeutic implications.
Core Innovation
The invention provides a method of treating cardiac disease by activating the growth hormone releasing hormone (GHRH) pathway, specifically through administration of a growth hormone releasing hormone receptor activating agent, such as a peptide and more particularly a synthetic peptide. The method targets cardiac diseases including myocardial infarction, myocardial ischemia, myocardial fibrosis, cardiac weakness, cardiac failure, and cardiac inefficiency, especially congestive heart failure.
The core finding demonstrated is that a synthetic GHRH agonist (GHRH-A) exerts cardioprotective effects in vivo following acute myocardial infarction (MI). The administration of GHRH-A improves cardiac structure and function, reduces infarct size, and markedly decreases cardiac fibrosis, an important determinant of poor prognosis in heart failure, without elevating circulating levels of growth hormone (GH) or insulin-like growth factor 1 (IGF-I). These effects appear direct and independent of the GH/IGF-I axis.
The problem addressed involves the controversy and unclear mechanisms regarding the cardioprotective effects of the GH/IGF-I axis and shortcomings of current therapies for congestive heart failure and post-MI left ventricular remodeling. Previous treatments with GH or GH secretagogues have shown inconsistent results, including potential adverse effects, whereas GHRH agonists offer a more physiological approach activating cardiac signal transduction pathways directly through GHRH receptors expressed on cardiomyocytes.
Claims Coverage
The patent includes two independent claims focusing on a method of cardiac repair post-myocardial infarction using synthetic peptides that activate the GHRH pathway. The main inventive features span the method of administration and the target cells.
Use of synthetic GHRH or GHRH agonists for cardiac repair
A method of initiating cardiac repair in a patient subsequent to myocardial infarction by administering a sufficient amount of a synthetic peptide that is GHRH or a GHRH agonist (GHRH-A) to activate the growth-hormone-releasing-hormone pathway of the patient.
Targeting cardiac myocytes for GHRH pathway activation
The method in which the targets of the synthetic GHRH or GHRH-A peptides are the cardiac myocytes of the patient, enabling direct activation of cardiac reparative mechanisms via GHRH receptors on the myocytes.
The claims cover a therapeutic method leveraging synthetic GHRH peptides to activate the GHRH signaling pathway directly in cardiac myocytes to effect cardiac repair following myocardial infarction, distinguished from classical GH or IGF-I based approaches.
Stated Advantages
GHRH agonists provide cardioprotective effects following acute myocardial infarction by improving cardiac structure and function and reducing infarct size.
GHRH-A markedly reduces cardiac fibrosis, which is strongly associated with poor prognosis in heart failure and severe arrhythmias.
The GHRH agonists exert direct cardiac effects independent of increases in circulating GH or IGF-I, potentially avoiding side effects associated with activation of the GH/IGF-I axis.
Treatment with GHRH-A improves hemodynamic parameters such as stroke volume, cardiac output, and ejection fraction while attenuating adverse left ventricular remodeling.
Documented Applications
Treatment of cardiac diseases such as myocardial infarction, myocardial ischemia, myocardial fibrosis, cardiac weakness, cardiac failure, and cardiac inefficiency, particularly congestive heart failure, by activating the GHRH pathway using synthetic peptides.
Interested in licensing this patent?