Can we precisely rewrite the genetic code - make a single DNA spelling change - in the liver of a human being for clinical effect? YES! Scientific milestone: VERVE-101 provides first proof-of-concept for in vivo DNA base editing in humans Clinical implication: It’s early but could open the way for an entire new way to treat heart disease; instead of daily pills/intermittent injections, a one-time intravenous infusion procedure to durably (possibly lifelong) lower LDL cholesterol; "surgery without a scalpel" Takeaways: 1. 10 patients with severe HeFH and ASCVD treated so far across 4 dose levels 2. Clinical effect on LDL-C (40% - 55% reductions) at potentially therapeutic doses 3. Dose-dependent reductions in blood PCSK9 protein and blood LDL-C 4. Durability so far out to six months, consistent with the pre-clinical data in NHP where the durability is out to 2.5y after a single treatment 5. Consistent with FDA guidance on patients to enroll in a Phase 1 study of gene editing products, we enrolled the sickest of the sick coronary disease patients 6. Safety profile revealed expected LNP-infusion related events: a) transient flu-like symptoms for a few hours after infusion; b) transient, reversible rise in LFTs after infusion 7. Two patients experienced CV events consistent with their underlying severe ASCVD 8. Safety profile supports continued development (DSMB have reviewed these data and requested to continue dosing) 9. These interim heart-1 data were submitted to FDA as part of IND package and we now have clearance to start study in U.S. 10. Next steps: finish dose escalation, complete dose expansion in 2024 11. Phase 2 start in 2025 for PCSK9 program Foremost, grateful to the patients who have volunteered and their families Thankful to the amazing @VerveTx scientific and clinical team (led by @andrew Bellinger), the investigators and study staff, the independent DSMB, and our partners P.S. Deepavali celebrates new knowledge and so thrilled to add today to our knowledge on the intersection of gene editing technology and cardiovascular disease $VERV @AHAScience @AHAMeetings @American_Heart #AHA23