Defining New Strategies for Therapy in Ampk Mutations and Hypertrophic Cardiomyopathy Implications for Personalised Medicine in Inherited Cardiac Disorders

Introduction: AMPK cardiomyopathy is an autosomal dominant inherited metabolic heart muscle disease 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.

Hypothesis: 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. Finally, a machine learning and neural network algorithm was developed to assign the currently available FDA approved drugs and chemical structures therein to modulate the downstream effectors from the candidate lists.
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.

Conclusions: 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 genetics. This real world platform shows a novel proof of concept means to provide potential candidates for a more tailored personalized therapy within inherited cardiac disorders.