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...

AI Technical Summary

Benefits of technology

The present invention proposes that a gene mutation and hypermethylation associated with cardiomyopathy leads to hypertrophy, fibrosis, and a hypoxic environment. The invention demonstrates that demethylation using agents such as 5-aza and 2′deoxy can increase MYBPC3 expression and reduce hypertrophy and fibrosis through various mechanisms such as direct or indirect up-regulation of MYBPC3 gene expression, resulting in reduced activation of a pro-fibrotic response in non-myocyte cells.

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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