Associate Professor of Medicine, Cardiology, and Genetics and Genomic Sciences and a faculty member of the Icahn Genomics Institute, USA
SMRTs* way to fix the heart
* Specific modified mRNA translation system
Host: S. Zacchigna
Mini-Biography: Lior Zangi, PhD, is an Associate Professor with Tenure at the Icahn School of Medicine at Mount Sinai, New York. He completed his education and training at the Weizmann Institute of Science, and Harvard University. Studies methods for delivering modified mRNA (modRNA) to the heart to induce cardiac regeneration, protection, or cardiovascular regeneration post ischemic injury. He has established a new method, modRNA based, for minimal invasive gene delivery into specific cell types and organs. He was the first to deliver modRNA into cardiac and skeletal muscle and pioneered using modRNA to treat ischemic heart disease. His invention led to the first successful phase 2 cardiac modRNA therapeutic clinical trial of Modenra/AstraZeneca (using VEGFA modRNA). In the last few years, these modRNA technology have been used for COVID19 vaccinations and promoting cardiovascular regeneration in ischemic heart disease. Currently, Prof. Zangi’s laboratory investigates mRNA delivery method into healthy or unhealthy specific cell types and organs, to fight different diseases such as heart failure and cancer.
Mini-Abstract: Ischemic heart failure (HF) secondary to myocardial infraction (MI) is a leading cause of mortality, mainly due to permanent loss of functional cardiomyocytes (CM) that are replaced by fibrotic scar post MI. This urgent unresolved medical need led scientists to evaluate whether induction of cardiac regeneration, protection or cardiovascular regeneration post cardiac ischemic injury can attenuate cardiac remodeling. Modified mRNA (modRNA) is an attractive and novel method to change gene expression in the heart. modRNA is currently being used around the globe for vaccination against COVID-19, and shown to be safe, highly efficient gene delivery approach. Our studies have shown the same and indicate that modRNA has therapeutic potential to treat ischemic diseases. Replacing 100% of Uridine with N1-Methylpseudouridine-5’-Triphosphate (1-mψU) in modRNA synthesis renders it non-immunogenic, with higher translation and RNase endurance than Uridine-based mRNA in cardiac cells and tissue. ModRNA delivery in vivo leads to high, immediate ( ~10 days) protein expression for ~5 days in several cardiac cell types, including CMs, or for ~10 days when injected, with or without ischemic injury, into the heart. To date, modRNA technology has been used to promote cardioprotection, CM proliferation that leads to cardiac regeneration, cardiovascular restoration, and attenuation of CF and cardiac hypertrophy post ischemic injury. We recently demonstrated that our specific modRNA translation system (SMRTs) delivers potent intracellular genes (e.g., cell cycle-promoting Pkm2), which are beneficial when expressed in one cell type (CM) but not others (non-CM), exclusively to CM. SMRTs is a platform that can be used outside the cardiac field, and hold the potential to be a key tool for genetic medicine in clinical and pre-clinical studies.
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