Cardiomyopathy is a leading cause of heart failure in children, and there are currently no effective treatments. Could emerging therapies that successfully target the root cause of the condition in adults also work well in children? That was the question Dr. James Ellis, a Senior Scientist in the Developmental & Stem Cell Biology program at The Hospital for Sick Children (SickKids), and Dr. Seema Mital, Scientific Lead at the Ted Rogers Centre for Heart Research and Head of Cardiovascular Research, Staff Cardiologist and Senior Scientist at SickKids, wanted to explore following their 2018 Ted Rogers Centre for Heart Research Strategic Innovation Award and funding from the Canadian Institutes of Health Research. The collaborative team of cardiologists, scientists, and bioengineers from SickKids, the University of Toronto, and the University Health Network published their exciting results this week in Cell Reports Medicine

Led by Caroline Kinnear (pictured above) from the Mital lab at SickKids, the team investigated possible treatments for pediatric hypertrophic cardiomyopathy (HCM). Hypertrophic cardiomyopathy is a genetic condition, with most cases caused by variants in myosin genes (MYH7 and MYBPC3). It is characterized by abnormal thickening of the heart muscle, which makes it harder for the heart to pump blood effectively. This condition can impact individuals of all ages but is a leading cause of heart failure and sudden cardiac death in children. 

Currently, the best treatments available for children with HCM include calcium channel blockers and beta-blockers, but they only provide symptom relief instead of treating the root cause. It was this issue that caught the attention of the team, and they decided to test if myosin-targeted drugs like myosin ATPase inhibitors recently approved or trialed in adults might also help children. 

To explore this, Dr. Ellis and team generated induced pluripotent stem cell (iPSC)-derived cardiomyocytes, which are beating heart muscle cells created in the lab after reprogramming cells from pediatric patients with HCM participating in the Heart Centre Biobank. As controls, cardiomyocytes were derived from the same stem cells after the genetic variants in MYH7 and MYBPC3 were corrected by gene editing. 

The HCM and control cardiomyocytes were tested by Dr. Mital’s group for their response to two different myosin inhibitors compared to the existing standard of care drugs like calcium channel and beta-blockers. They looked at the effect of the drugs on cell contractility, relaxation, and other cardiac function abnormalities seen in HCM cells. Myosin inhibitors fully repaired the abnormalities and normalized cardiomyocyte function, an effect that was not seen with standard drugs. Moreover, when compared to cells in which the variation had been corrected by gene editing, the drugs were as effective as genetic correction of the cells. Importantly, the myosin inhibitors were effective in cardiomyocytes from patients with variants in a single gene, and also in those with genetic variants in both copies of a gene, or in two different genes. 

The team engaged Dr. Milica Radisic, Professor and Canada Research Chair of Functional Cardiovascular Tissue Engineering, to validate the effects of myosin inhibitors in a 3D tissue model. Dr. Radisic’s work showed that blocking myosin ATPase consistently made the heart tissues behave more like normal tissues, confirming that the drug had the desired effect. “The results are very promising” commented Dr. Radisic. “We’re hopeful that future testing with this patient population will build upon what we’re seeing here.” 

The outcome of this new study paves the way for myosin inhibitor drug trials in pediatric HCM patients to see if this might be a pathway to preventing heart failure and sudden cardiac death. For Dr. Ellis, Canada Research Chair in Stem Cell Models of Childhood Disease, the study “shows how stem cells can model pediatric disease in the lab and then advance precision medicine by identifying the optimal treatment for each child’s genetic variant.” According to Dr. Mital, Heart & Stroke Foundation of Ontario Chair in Cardiovascular Science, “The finding that a myosin-targeted drug can mirror the effects of genetic rescue shifts the paradigm of HCM treatment from merely symptom-relief to tackling the underlying cause of conditions.” 

On the heels of this new publication, an international clinical trial sponsored by Bristol Myers Squibb is set to launch in 2024. The trial aims to expedite the approval and delivery of these treatments to children with HCM as soon as possible.