Hypertrophic cardiomyopathy (HCM) is the most common of hereditary cardiac conditions and is related to mutations in sarcomere proteins, the most frequent of which is MYBPC (cardiac myosin protein C). While MYPB-C mutations are associated with HCM, there is a marked heterogeneity in phenotypic responses to mutations of this gene, even within families, and this could be explained by epigenetic factors such as hypermethylation. UCD researchers have shown that the DNA methylation inhibitor 5-azacitidine (5-aza) improves cardiac function, including hypertrophy and diastology, in a murine animal model (SHR, spontaneously hypertensive rat, model) and this is associated with up-regulation of MYBP-C, and more surprisingly actin alpha1 skeletal muscle (ACTA1), gene expression in cardiomyocytes. Therefore, DNA methylation inhibitors may represent a novel therapeutic strategy for the prevention and treatment of HCM, in particular the Orphan indications HOCM and FHCM. 5-aza is a hypomethylation agent that could be repurposed for Orphan indications in HCM.

UCD researchers have found that DNA methylation inhibitors such as 5-aza improve cardiac function in the SHR animal model. Figure 1 shows the effect of 5-aza treatment in the SHR model on echocardiographic parameters and improvement in hypertrophic and diastolic parameters. Figure 2 shows that 5-aza up-regulates expression of MYBP-C and ACTA1 in cardiac tissue in these SHR animals. Up-regulation of MYBP-C and ACTA1 by 5-aza was also shown in vitro using cardiac myoblast cells

There is a significant unmet need for pharmacological therapies that move beyond symptom management and can also inhibit the progression of left ventricular hypertrophy. Repositioned drug for development initially in Orphan indications of HCM. 5-aza is marketed as an anti-cancer therapy by Celgene as Vidaza. An oral formulation is in development. Research results indicated that the hypomethylation effect may be at a lower dose than the cytotoxic effect. Therefore, some dose related toxicities may be avoided and the cardiovascular indication differentiated from the cancer indication.

Priority patent application UK 1309444.6, filed on 5/9/2013