Improved CRISPR base editing therapy cuts high cholesterol

A CRISPR genome editing therapy provides sustained reductions in 'bad' cholesterol in people with inherited high cholesterol or premature coronary artery disease, an early-stage clinical trial shows.

A follow-up analysis of the one-time genome editing therapy VERVE-102, designed to permanently switch off the PCSK9 gene in the liver, has shown durable reductions in blood low-density lipoprotein (LDL) cholesterol, often referred to as 'bad' cholesterol. Results from the Phase 1b Heart-2 trial, involving 35 patients with premature coronary artery disease or with heterozygous familial hypercholesterolaemia (a genetic condition that impairs the body's ability to clear LDL cholesterol from the bloodstream, increasing the risk of heart disease), showed dose-dependent reductions in LDL cholesterol, with mean reductions of up to 62 percent in the highest-dose group. The findings were published in the New England Journal of Medicine.

'Twenty years ago, genetics showed us that people born with PCSK9 naturally turned off have low LDL cholesterol for life and are remarkably protected from heart attacks,' said Professor Sekar Kathiresan, Eli Lilly senior vice president and co-founder of Verve Therapeutics. 'The Heart-2 results provide early clinical evidence that a single dose of VERVE-102 may mimic the LDL cholesterol lowering effects of PCSK9 cardioprotective variants, potentially transforming cardiovascular care from chronic management to a one-time treatment.'

VERVE-102 uses the same base-editing technology as its predecessor, VERVE-101 (see BioNews 1288 and 1315). However, it incorporates an improved lipid nanoparticle to encapsulate the therapy and deliver it more safely by relying on specific receptors on the surface of liver cells. Once inside the cell, VERVE-102 makes a single DNA base change in the PCSK9 gene, permanently switching it off. Because PCSK9 (the enzyme encoded by the gene of the same name) normally promotes the breakdown of LDL receptors in the liver, lowering PCSK9 levels allows more LDL receptors to remain active and remove LDL cholesterol from the bloodstream.

The Heart-2 trial is an ongoing open-label, single-ascending-dose study designed primarily to assess the safety and tolerability of VERVE-102. Thirty-five participants received a single intravenous infusion across six dose levels ranging from 0.3 mg/kg to 1.0 mg/kg. At the data cut-off, 15 participants had been followed for at least one year, and some for up to 18 months. Researchers reported dose-dependent reductions in circulating PCSK9 of 51 to 88 percent and reductions in LDL cholesterol ranging from nine to 62 percent, with the effects appearing durable throughout follow-up.

Researchers reported no dose-limiting toxic effects. Mild-to-moderate infusion-related reactions were observed, along with temporary changes in liver function blood tests, and one participant developed aspiration pneumonitis, a type of lung inflammation caused by inhaling stomach contents. Participants are expected to enrol in a long-term follow-up study lasting up to 15 years, while Eli Lilly plans a Phase 2 trial later this year.

'This therapy is likely to revolutionise our management of lipids and cardiovascular disease, as a one-off permanent treatment could in the future obviate the need for daily pills,' said Dr Jaimini Cegla, consultant in metabolic medicine at Imperial College Healthcare NHS Trust, London, and a co-author of the study. 'This novel approach is a game-changer for people living with high cholesterol and heart disease.'