Regeneration-based therapy for the treatment of ventricular tachycardia: a potential alternative to catheter ablation
Description: Ischemic heart diseases are the leading cause of death world-wide. One of the major contributor of IHD mortality is sudden cardiac death (SCD). SCD is attributed to malignant ventricular tachycardias (VT), those arrhythmias arise from portion of the myocardium that is intertwined with scar tissue. Those peninsulas of viable myocardium are the source of re-entry pathways, leading to VT. The most effective treatment available to eliminate re-entry pathways and prevent SCD is catheter ablations. This treatment successfully terminate VT by removing the remaining viable myocardium, leaving the patients with more scar. Other treatments, like internal defibrillator or pharmacological therapies are also used to manage VT and reduce the risk of SCD but they are not aimed to treat the underlying cause: the loss of electrical conduction due to scar formation. Human stem cell-derived cardiomyocytes (hPSC-CMs) and regenerative-based therapies represent the next chapter in modern medicine. The Murry Lab has extensive expertise in hPSC-CM transplantation and it was one of the first lab to demonstrate their application for IHD. HPSC-CMs can indeed be manufactured at large scale and are now tested in the first clinical trials. Because of the immature state of this cells, however, transient arrhythmias arise after transplantation, which is prohibitive for their use in arrhythmogenic disorders like VT post-MI. We have recently published a gene-editing approach that result in hPSC-CMs that are electrophysiologically more mature, i.e., only beat upon external stimulation. Those quiescent-yet-excitable hPSC-CMs can remuscularized the infarcted heart of nonhuman primate, without causing arrhythmias. We want to build on this discovery by engineering a well-characterized human induced-pluripotent stem cell line using base editing, this will increase the reproducibility of our results, provide a streamline gene-editing strategy that can be easily replicated in patient-derived hiPSCs as well reduce the risk of genotoxicity due to double-stranded breaks mediated by Cas9. We will then inject those cells into a model of ischemia/reperfusion developed in collaboration with Drs. Ripplinger, Davis and Nazer. These results will provide for the first time preliminary evidence that hPSC-CMs technology can be used for arrhythmogenic disorders, beyond IHD: this regenerative-based approach might represent a safer and more effective alternative to catheter ablation and heart transplantation.
Funder: American Heart Association
Amount: $300,000
Funding type: research
Funder scheme: Second Century Early Faculty Independence Award
Start date: 2024-10-01
End date: 2027-09-30
Investigators: Silvia Marchiano, Silvia Marchiano
Institution: University of Washington
Subfield: Molecular Biology
Domain: Life Sciences
Funded outputs count: 4
Funder award ID: 24SCEFIA1253490
OpenAlex ID: G2880468087