Date: 3rd July 2020
Coronary heart disease (CHD) is the leading cause of death worldwide, killing over 7 million people each year. The primary cause of CHD is atherosclerosis, a condition where the arteries become narrowed and hardened due to an accumulation of plaque around the artery wall. Two leading factors in atherosclerosis are high low-density-density (LDL) cholesterol and high triglyceride-rich lipoproteins. Now Verve Therapeutics, report preclinical proof-of-concept data in non-human primates that demonstrate the successful use of base editing as a new treatment approach for coronary heart disease.
Verve Therapeutics is a a next-generation cardiovascular company, based in Cambridge, US. Verve brings together human genetic analysis and gene editing in their singular purpose to protect the world from heart disease.
DNA base editors are becoming popular tools for gene editing, they comprise of a catalytically disabled nuclease fused to a nucleobase deaminase enzyme, which can convert one base or base pair into another permanently, without creating a double-stranded DNA break.
Now the team at Verve have used an adenine base editor (ABE) mRNA and an optimised guide RNA delivered in a nanoparticle via a single intravenous infusion into primates. The aim; to switch off either proprotein convertase subtilisin/kexin type 9 (PCSK9), a gene whose protein product elevates blood LDL cholesterol, or angiopoietin-like protein 3 (ANGPTL3), a gene whose protein product elevates blood triglyceride-rich lipoproteins.
The studies were performed in 14 primates, and split into two groups with each group receiving the drug to target either the PCSK9 gene or the ANGPTL3 gene.
At two weeks post treatment the whole liver was assessed for editing, and blood protein and lipid levels were measured.
The program targeting PCSK9 showed an average of 67% whole liver PCSK9 editing. This resulted in an 89% reduction in plasma PCSK9 protein and a 59% reduction in blood LDL cholesterol levels.
The program targeting ANGPTL3 showed an average of 60% whole liver ANGPTL3 editing, with a 95% reduction in plasma ANGPTL3 protein. Here, a 64% reduction in blood triglyceride levels and 19% reduction in LDL cholesterol levels was observed.
Furthermore, in primary human hepatocytes, there was no evidence of off-target editing.
Conclusions and future applications:
The findings support Verve’s mission to develop one-time gene editing medicines that can safely edit the adult human genome. The report was presented at the International Society for Stem Cell Research (ISSCR) 2020 Virtual Annual Meeting.
Verve has several gene editing programs underway and will choose a lead program to carry forward to clinical trials within the next 3 years.
We are currently entering a new exciting phase for base editors. They were developed by David Liu and Alexis Komor, at Harvard University, US, in 2016, four years after the CRISPR-Cas system was first harnessed for gene editing. Now, it seems the technology is gathering momentum and the applications for base editors is accelerating.
We have recently seen scientists demonstrating the feasibility of multiplexed base editing for polygenic disease modelling in primate zygotes, allowing editing of up to three targets at a time. They have also been successfully used in vivo to repair a single nucleotide mutation in deaf mice, partially restoring hearing loss. Supportive tools are also being developed around base editors to optimise safety and precision, such as a machine learning (ML) model, called BE-Hive, that accurately predicts base editing outcomes and determines which base editor is ‘best-in-class’.
Together this work is driving base editors towards the clinic, hopefully in the not so distant future.
For more information please see the press release from Verve Therapeutics.
