DEVELOPING A HUMAN STEM CELL-DERIVED HEART MODEL TO CHARACTERIZE A NOVEL ARRHYTHMIA SYNDROME (CCC-210)

What problem does your idea solve?: Sudden cardiac arrest (SCA) is a devasting heart event with a 10% survival rate. In young persons and athletes, inherited arrhythmias may account for up to 50% of unexplained SCA cases. In 2021, a distinct inherited arrhythmia syndrome, called calcium release deficiency syndrome (CRDS), was described in patients carrying loss-of-function RyR2 variants. These patients present with SCA but appear normal on the exercise stress test. As a newly discovered arrhythmia syndrome, there is a tremendous gap in knowledge about disease mechanisms, diagnostics, and appropriate treatments, which must be addressed to avoid preventable morbidity and mortality.

We have developed, to our knowledge, the world’s first human stem-cell based heart model to understand the molecular mechanisms of this disease, perform “clinical trials in a dish” to identify candidate treatments, and test out various electrical stimulation protocols that could be applied in clinical electrophysiology (EP) labs.

At what stage of development are you? Have you tested your innovation? : We have successfully generated the stem cell model using CRISPR-Cas9 genome editing, which carries the heterozygous RyR2 p.A4142T genetic variant, found in the largest identified CRDS family with several members suffering from sudden death. We have also made isogenic control cell lines to allow for direct comparison, with the only genetic difference being the p.A4142T point variant. These have been successfully made into beating heart cells in a dish.

We have performed preliminary studies subjecting these cells to an “exercise stress test” in a dish using electrical pacing + the β-agonist isoproterenol, and to the experimental diagnostic electrical stimulation protocol (LBLPS), using multielectrode array (MEA) technology. MEA captures field potentials, which are equivalent to the QRS and T signals on an electrocardiogram, and can accurately detect arrhythmia. Currently, we are utilizing high speed optical mapping to study at how this variant affects cellular voltage, calcium dynamics, and conduction velocity.

Explain how and where this impacts the cardiovascular care patient/workplace.: First, our model will serve as a personalized therapeutics platform to test the efficacy and safety of approved and novel antiarrhythmics including β-blockers, flecainide, and calcium channel blockers. Given that the FDA approved using pharmacogenomic studies in stem-cell based heart models for direct translational use in 2023, our findings will have direct relevance to patients, inform clinical decision making, and reduce treatment failure for a condition where medical management data is scarce.

Additionally, our human-based model can be used as for bench-to-bedside and bedside-to-bench mechanistic studies. This can be superior to animal models given the human genomic background. Since we can electrically stimulate the cells using various protocols and see how cellular calcium and voltage dynamics are affected, we can identify which protocols may be most effective in unmasking the arrhythmia instead of exercise stress tests, and these protocols could be applied in the clinical electrophysiology (EP) labs.

Why do you think your innovation should receive the $1,000 prize? : We believe that our translational modal to uncover the molecular mechanisms of and potential treatments for CRDS, a novel arrhythmia syndrome with many questions unanswered, is truly revolutionary and can directly impact patient care. Without having a robust human-based model to test therapeutics, clinicians would have to rely on a trial-and-error approach for management, which could pose significant harm to patients and lead to likely preventable treatment failure. Our model is its first of its kind and can address not only molecular mechanisms of disease but also treatment options and diagnostic tests that can be tested in the EP lab. We are leveraging a personalized medicine approach with patient-derived stem cells that capture the genomic background and complexity of patients, which other model systems cannot capture. Thus, our model is a huge step towards the future of clinical care, where treatments are targeted, personalized, and evidence-based.

If you should be the winner, what will you use the prize money for?: Winning the prize money would be an honour that would further emphasize the importance of our innovation. Performing the basic science research our technology is based on can be very expensive. Since we plan on performing a robust, high-throughput therapeutics study, I would use $500-750 to purchase the following drugs from Sigma-Aldrich which are not available at our lab: nadolol, metoprolol, and verapamil. Notably, our team of graduate students has worked diligently and tirelessly on making this translational model possible, so I would allocate $150-$250 to treat our 8-member team to a dinner that elevates team morale and bonding.

Provide a brief overview of your pitch. How are you going to sell this idea to the dragons and the audience?: I, Saif Dababneh, will be presenting this pitch. First, I will start off a patient story related to cardiac arrest as a result of an inherited arrhythmia. I will then briefly highlight the background behind cardiac arrest, pathogenic genetic variants, and how patients and families are affected by inherited arrhythmias. I will then introduce CRDS, spotlight the large knowledge gap in this novel arrhythmia syndrome, and introduce the technology we’re using and its transformative capability to address the knowledge gap. I will explain how our technology works, show videos of patient-derived stem cells that have become beating heart cells in a dish, and show what we have been done experimentally so far. I will touch on what our model can achieve in the future, and how winning this prize could not only directly impact our innovation but also transform future care for cardiovascular patients.