Defining new strategies for therapy in PRKAG2 mutations and hypertrophic cardiomyopathy: implications for personalised medicine in inherited cardiac disorders

Introduction PRKAG2 cardiomyopathies  are autosomal dominant inherited  heart muscle diseases often characterized by left ventricular hypertrophy (LVH), progressive conducting abnormalities and ventricular pre-excitation... [ view full abstract ]

Introduction

PRKAG2 cardiomyopathies  are autosomal dominant inherited  heart muscle diseases often characterized by left ventricular hypertrophy (LVH), progressive conducting abnormalities and ventricular pre-excitation Wolff-Parkinson-White [WPW] syndrome. However, AMPK mutations especially in the gamma 2 subunit are accompanied with chronotropic incompetence, glycogen accumulation and advanced heart blocks leading to premature pacemaker implantation. Therapeutic options to better control the arrhythmic potential and the underlying biological sequelae from such mutations remain an enigma. We investigate the application and development of a novel drug discovery  platform to elucidate the mechanism of this disorder and a potential therapy which was taken into the clinic as an example of a bench to bedside protocol. 

Methods

Human Induced Pluripotent Stem cells (hIPSc) were derived using a novel protocol from urine and subsequently differentiated to cardiomyocytes using a chemically defined protocol. This was used as the  modelling tool for this study. An integrated approach utilising transcriptomic and proteomic data as a platform was used to define candidate proteins implicated within the mutant lines. Isogenetic lines were also produced using a modified Crispr-Cas9 system. In addition, homozygote  gene correction of underlying mutant lines was also undertaken with review of potential  off targets and karyotype status.

Results  

Carvedilol was the only drug that was defined as having a novel mechanism of action on AMPK and on AMPK mutations directly using our platform, this was not a class effect. 

One year follow up data of the patient showed statistically significant reduction in atrial (P=0.01) and ventricular (P=0.01) arrhythmia burden. Furthermore, there was a substantive reduction in BNP and a general increase in LVEF overall.

Discussion

This study represents the first of its kind to clinically verify drugs specific for therapy within the spectra of personalized medicine. It is also the first example of compound mutation correction in human cardiomyocytes as a means to better elucidate mechanism of action from mutation to clinical output. This real world platform shows a novel proof of concept means to provide  potential candidates for a more tailored personalized therapy in cases of inherited cardiac disorders whereby therapy remains an overwhelming goal.