Spotlight on Gene and Molecular Therapies at ESC 2026, With Steven Nissen, MD

Gene and molecular therapies are moving from proof-of-concept to durable, clinically meaningful effect in lipid disorders once considered untreatable at the genetic level, spanning severe familial hypercholesterolemia, ANGPTL3-driven dyslipidemia, and elevated lipoprotein(a). A late-breaking session at the European Society of Cardiology (ESC) Congress 2026 in Munich, Germany, featured key presentations charting this progress.

Steven Nissen, MD, of Cleveland Clinic, moderated the session and shared his takeaways with HCPLive, highlighting presentations spanning gene therapy for homozygous familial hypercholesterolemia (FH), CRISPR-based editing of ANGPTL3, and a small interfering RNA (siRNA) targeting lipoprotein(a).

AAV8 Gene Therapy for Homozygous Familial Hypercholesterolemia

Ting Li, of the First Affiliated Hospital of Xi'an Jiaotong University, presented results of an AAV8-mediated gene therapy for homozygous familial hypercholesterolemia.¹

"The adenovirus vector for replacing the LDL cholesterol receptor gene was a pretty dramatic effect. It was small, it was only 10 patients. They had homozygous familial hyperlipidemia with LDL cholesterols close to 400. They had 80-90% reductions in LDL cholesterol when they had this gene therapy," Nissen explained. He noted the treatment required corticosteroids and other therapies to manage liver enzyme elevations, calling the approach a promising step for a devastating disease.

CTX310 Durability in CRISPR-based ANGPTL3 Editing

Luke Joseph Laffin, MD, of Cleveland Clinic, presented 1-year durability data for CTX310, a CRISPR-Cas9 gene-editing therapy targeting ANGPTL3.² According to Nissen, Laffin presented results from 1 year after initial treatment with the ANGPTL3 approach, showing about a 50% reduction in triglycerides and a 50% reduction in LDL cholesterol persisting out to a year.

"This is important because the liver undergoes recycling. The cells regenerate maybe 15% per year, and so if the cells that are not edited are replicating more commonly than the cells that are, in fact, treated, then the effect would go away, but it didn't. So it suggests that there's a very high level of editing of the hepatocytes with this CRISPR-based therapy...," Nissen said, noting the 1-year data are set to appear in a short paper in the New England Journal of Medicine.

CTX310 previously demonstrated dose-dependent reductions in triglycerides and LDL cholesterol in an initial phase 1 trial published in the New England Journal of Medicine, without dose-limiting toxic effects related to the therapy.³

Kylo-11 and Durable Lipoprotein(a) Reduction

Ashish Sarraju, MD, of Cleveland Clinic, presented final data from a first-in-human study of Kylo-11, an investigational siRNA targeting lipoprotein(a).⁴ Nissen said the Kylo-11 data were surprising: the therapy lowered lipoprotein(a) by as much as 97%, and at doses of 225 mg or greater, the effect persisted after a single injection out to 48 weeks, essentially a year, with no evidence of rebound.

"It's the most durable, high-intensity reduction in lipoprotein(a) we've seen yet," Nissen said. "It's very early, it's phase 1, lots more work has to be done, but this field just keeps progressing as we get more and more understanding about how to build these small interfering RNAs so that they have the kind of effects that we're looking for."

References

1. Li T. AAV8-mediated gene therapy for homozygous familial hypercholesterolemia. Presented at: ESC Congress 2026, Late-Breaking Clinical Trials: Rewriting Cardiovascular Disease on Gene and Molecular Therapies; Munich, Germany.

2. Laffin LJ. Durability of Effects of CTX310, a CRISPR-Cas9 Gene Editing Targeting ANGPTL3. Presented at: ESC Congress 2026, Late-Breaking Clinical Trials: Rewriting Cardiovascular Disease on Gene and Molecular Therapies; Munich, Germany.

3. Phase 1 trial of CRISPR-Cas9 gene editing targeting ANGPTL3. N Engl J Med. 2025;393(21):2119-2130. doi:10.1056/NEJMoa2511778

4. Sarraju A. Extremely Long Duration Lp(a) Reduction Following a Single Dose of Kylo-11: Final Data from a First-in-Human Study. Presented at: ESC Congress 2026, Late-Breaking Clinical Trials: Rewriting Cardiovascular Disease on Gene and Molecular Therapies; Munich, Germany.