Therapies for cardiomyopathy

Abstract

The present invention relates to therapies and therapeutic agents for use in the treatment of cardiomyopathies. In particular, the invention is concerned with, but not limited to therapies and therapeutic agents for use in the treatment of hypertrophic cardiomyopathy. Such therapeutic agents comprise hypomethylating agents.

Description

FIELD OF THE INVENTION[0001]The present invention relates to therapies and therapeutic agents for use in the treatment of cardiomyopathies. In particular, the invention is concerned with, but not limited to therapies and therapeutic agents for use in the treatment of hypertrophic cardiomyopathy.BACKGROUND TO THE INVENTION[0002]The strict definition of cardiomyopathy is a myocardial disorder in which heart muscle is structurally and functionally abnormal. The vast majority of cardiomyopathy is extrinsic (external causes) and of these, the ischemic form is the most common. The term “ischemic cardiomyopathy” typically refers to remodeled and hypertrophied myocardium as a result of inadequate oxygen delivery to the myocardium, with coronary artery disease being the most common cause. Ischemic cardiomyopathy may therefore be regarded as a first subtype of cardiomyopathy.[0003]The term “cardiomyopathy” is also sometimes used to specifically describe non-ischemic forms of cardiomyopathy, o...

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Benefits of technology

[0039]Bacanamwo et al. Circulation (2007) vol 116, p124 describes demethylation effects of 5aza on genes associated with hypertension in an Angiotensin II hypertensive disease model, in which an antihypertensive effect of 5aza by putative demethylation effects on genes associated with hypertension such as 11β-HSD2 which was methylated in the arteries and kidneys is reported. The authors conclude the data “suggest that DNA methylation plays a critical role in the coordinate regulation of genes involved in the pathogenesis of hypertension and vascular remodeling.” However, hypertension is known to increase hypertrophy and fibrosis and antihypertensive therapies are well known to reduce hypertrophy and fibrosis. The effects described in the present invention are not dependent on hypertension. All genes can be methylated and there is no way to predict that because of the described antihypertensive effects on 11β-HSD2, there could be an antihypertrophic effect of the 5aza independent of hypertension, nor a beneficial effect on, for example, the expression of MYBPC3. Taylor et al New England Journal of Medicine (2004) vol 351 pp 2049-2057, describes the antihypertrophic effects of isosorbide dinitrate and hydralazine in combination. Hydralazine is an antihypertensive agent and antihypertensive agents can reduce hypertrophy and fibrosis. Isosorbide dinitrate has independent pharmacological effects which contribute to and promote BP reduction and protect against myocardial ischemia. There is no evidence that the observed effect on cardiac hypertrophy is related to hydralazine alone and also to epigenetic effects. US A 2011 / 0319466 describes the use of a HDAC inhibitor (phenylbutyrate) in combination with an ACE inhibitor for the treatment of heart failure, cardiac hypertrophy and cardiac dysfunction. Esha et al. FASEB Journal (2002) vol 16, pA491 describes a DNMT inhibitor (5azaDC) to manage ischemic injury in dogs and an improvement in post-ischemic myocardial function and “scar formation.” There is no disclosure of an impact on hypertrophy. Furthermore, hypertrophy can occur in the absence of ischemia and in the case of familial cardiac hypertrophies, the pathophysiological driver is not ischemia.

[0040]US A 2012 / 0014962 describes the antifibrotic effects of DNMT inhibitors on models of liver fibrosis and antifibrotic effects of the drug on cardiac fibrosis and endomyocardial fibrosis. The antifibrotic effects of DNMT inhibitors 5aza and 5azaDC are known, but this is quite distinct to the antihypertrophic effects described in the present application. Kao et al Laboratory Investigation (2011) vol 91, pp 1291-1297 describes the DNMT inhibiting effects of hydralazine on SERCa2. There is no evidence of an antihypertrophic effect independent of SERCAa2 and so it is not possible to ascribe the reduction in cardiac hypertrophy to DNA demethylation, nor could one anticipate the effects of 5aza on MYBPC3. UA A 2009 / 0105168 describes the use of a DNMT inhibitor for ischemic injury and treatment of hypertrophy and post ischemic injury including cardiac surgery, stroke and myocardial infarction. As mentioned above hypertrophy can occur in the absence of ischemia. In the case of familial cardiac hypertrophies, the pathophysiological driver is often not ischemia.

Problems solved by technology

Prognosis depends on aetiology, but is generally poor.

This is particularly the case in view of the fact that many cardiomyopathies are multifactorial in nature, which makes it difficult to place every cardiomyopathy in a discrete class.

Nonetheless, the same study also showed that HCM with fibrosis is associated with >3 fold increase in cardiovascular death, unplanned cardiovascular admission, sustained ventricular tachycardia or ventricular fibrillation, or appropriate implantable cardioverter-defibrillator discharge.

Furthermore, within the patient cohort with fibrosis, a greater extent of fibrosis was associated with worse outcome.

Other work has associated the mutations with other pathologic changes such as ischemia—for example compromised coronary flow due to hypertrophy, microvascular dysfunction, increased oxidative stress, and increased metabolic demands imposed by abnormal biophysical properties of mutant sarcomeres resulting in an imbalance of oxygen demand and supply.

Recent data in mouse models of HCM has shown that sarcomere gene mutations activate proliferative and pro-fibrotic signals in non-myocyte cells from HCM mouse hearts resulting in increased levels of pro-fibrotic proteins including TGFβ resulting in fibrosis.

There is no evidence of an antihypertrophic effect independent of SERCAa2 and so it is not possible to ascribe the reduction in cardiac hypertrophy to DNA demethylation, nor could one anticipate the effects of 5aza on MYBPC3.

Thus, what can be used to treat fibrosis cannot necessarily be used to treat all instances of HCM.

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