In this conversation, Daniel Belkin and Mitch Belkin speak with Sekar Kathiresan, MD, about using gene editing medications to treat cardiovascular disease. We discuss Dr. Kathiresan's company Verve Therapeutics, which has pioneered a lipid nanoparticle delivery system of a CRISPR-based gene editing technology. We delve into the pathophysiology of cardiovascular disease, the role played by LDL and the LDL receptor in atherosclerosis, the genetics underlying monogenic and polygenic risk for myocardial infarction, CRISPR and the future of gene editing technologies, and Verve's ongoing phase I trial of a PCSK9 gene editing medication (VERVE-101) in humans.

Who is Sekar Kathiresan?
Dr. Sekar Kathiresan, a cardiologist, geneticist, and the CEO and co-founder of Verve Therapeutics. Verve Therapeutics is a company pioneering a new approach to the treatment of cardiovascular disease with single-dose gene editing medications. Prior to co-founding Verve, he served as the director of the Massachusetts General Hospital Center for Genomic Medicine and was a Professor of Medicine at Harvard Medical School.

1:26 - Introduction: Sekar Kathiresan's background
2:39 - Pathophysiology of cardiovascular disease
4:35 - LDL as the primary driver of cardiovascular disease
6:14 - What are the different types of lipoproteins?
11:00 - Common medications that lower LDL (Statins, PCSK9 inhibitors, Ezetimibe, Bempedoic acid)
14:29 - Genetics underlying cardiovascular disease risk (monogenic vs. polygenic risk)
16:50 - How the LDL receptor works
21:55 - Cardiovascular resistance genes (including PCSK9, ANGPTL3, and 6 other genes)
26:23 - What is CRISPR?
29:31 - How do PCSK9 and ANGPTL3 work?
34:32 - How to deliver gene editing medications to the liver? (answer: lipid nanoparticles)
39:21 - Single-dose gene editing medications: Introducing VERVE-101
43:58 - Potential concerns with systemic gene editing (editing other organs, off target editing, guide RNA independent DNA editing)
49:30 - Major challenges with developing VERVE-101
51:30 - Phase I human trials
57:06 - Toxicities and side effects of VERVE-101
1:01:01 - Rapid fire questions


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