Use of the insulin-like-growth factor I splice variant MGF for the prevention of myocardial damage

Abstract

The invention relates to the use of a Mechano Growth Factor (MGF) polypeptide or a polynucleotide encoding an MGF polypeptide in the manufacture of a medicament for the prevention or limitation of myocardial damage in response to ischemia or mechanical overload of the heart by preventing or limiting apoptosis in the myocardium.

Description

[0001] The present application is a divisional of U.S. application Ser. No. 10 / 504,078, filed Oct. 20, 2004 (pending), which is a U.S. national phase of international application PCT / GB03 / 00537, filed Feb. 6, 2003, which designated the U.S. and claims benefit of GB Application No. 0202906.4, filed Feb. 7, 2002, the entire contents of each of which is hereby incorporated by reference in this application.FIELD OF THE INVENTION [0002] This invention relates to the use of polypeptides derived from the sequence of the IGF-I splice variant MGF and polynucleotides encoding such polypeptides in the prevention of myocardial damage following ischemia and / or mechanical overload. BACKGROUND OF THE INVENTION Ischemic Heart Disease [0003] Ischemia occurs when an artery supplying oxygenated blood to a muscle or other organ becomes occluded. This diminishes the ability of the affected organ to function and may involve cell death in the area whose blood supply is reduced. [0004] Ischemic heart dise...

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Benefits of technology

[0014] Herein, we show that MGF is strongly expressed in the infarcted area following ischemia in rat and sheep heart. In contrast to the situation for LIGF-I, we have also shown that MGF expression coincides with the immediate recovery stage following mechanical overload and transient ischemia. MGF expression is therefore more rapid than L-IGF-I expression. We have also shown that MGF expression is induced in cardiac myocytes undergoing apoptosis, that stable transfection of the cardiac-like cell line H9C2 with MGF prevents apoptosis and obtained evidence that MGF induces a hypertrophic phenotype in myocytes in vitro.

[0015] Additionally, we have shown that prolonged expression of MGF in cardiac myocytes is associated with suppression of thick filament proteins of myofilaments but not thin filament proteins. This acts to dedifferentiate the myocyte. We conclude that MGF expression results in remodeling of the infarcted region, i.e. that by dedifferentiating the myocyte, MGF facilitates the repair process.

[0017] Our findings herein show that MGF is activated in response to cardiac tissue damage and has a repair function in the ischemic and / or overloaded heart. In turn, this shows that, in addition to previously noted utilities, can be used to protect against myocardial damage from apoptosis in response to ischemia / overload. In this connection, there are two aspects to the cardiac repair process, namely prevention of apoptosis and hypertrophy of the surviving cardiomyocytes in the damaged regions to compensate for the loss of cardiac muscle cells.

[0018] Rapid administration of an MGF polypeptide after a heart attack is particularly desirable, and longer term treatment can also be effected, especially by delivering an polynucleotide encoding an MGF polypeptide to maintain levels of MGF in the cardiac muscle after initial administration of the polypeptide.

Problems solved by technology

However, under certain conditions a transition to pathological hypertrophy can take place in which there is increased myocardial mass but decreased cardiac performance.

The cells of the ventricles revert back to expressing the embryonic isoforms of the contractile genes, which results in more rapid energy utilization.

To further exacerbate the problem, other forms of myocardial injury that can occur often result in myocyte cell death apoptosis) resulting in the loss of functioning myocytes.

However, all of this work explicitly involved recombinant IGF-I of the liver or systemic type, or failed to recognise the existence of multiple IGF-I isoforms.

Along with muscular dystrophy and other skeletal muscle disorders, WO97 / 3397 (U.S. Pat. No. 6,221,842) also mentions the possibility of prevention of cardiac disorders, diseases where promotion of cardiac muscle protein synthesis is a beneficial treatment, cardiomyopathies, acute heart failure or acute insult including myocarditis or myocardial infarction, and improving cardiac output by increasing heart / volume; but does not provide experimental findings linking MGF to cardiac, as opposed to skeletal, muscle.

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