The US biotechnology company Verve Therapeutics presented a new preclinical proof-of-concept data on successful use of base editing to turn off a gene in the liver and thereby lower blood levels of either LDL cholesterol or triglyceride-rich lipoproteins, two factors leading to coronary atherosclerosis.
Verve, which is exclusively focused on the development of next-generation cardiovascular medicines, generated this pathbreaking data in non-human primates and presented the same at the International Society for Stem Cell Research (ISSCR) 2020 Virtual Annual Meeting in the last week of June.
With this data, the company is targeting the development of a one-time gene-editing medicine that safely edit the adult human genome and mimic naturally occurring cardioprotective variants to permanently knock out cholesterol-raising genes in the liver and treat coronary heart disease.
“At Verve, our goal is to develop medicines, given once in life, that precisely edit targeted genes in the liver to permanently reduce LDL cholesterol and triglyceride levels in adults with coronary heart disease, the leading cause of death in the US and worldwide,” said Dr Sekar Kathiresan, co-founder and chief executive officer of Verve Therapeutics, while presenting the results of its recent studies utilising adenine base editing (ABE) technology, in which substantial lowering of plasma LDL cholesterol or triglycerides was demonstrated in non-human primates.
Base editing is a gene-editing technology developed to enable precise and permanent rewriting of a single DNA letter in the genome. Verve Therapeutics had licensed this technology from Beam Therapeutics in 2019.
First successful application
“These proof-of-concept data, which to the best of our knowledge represent the first successful application of the base editing technology in non-human primates, show that we can safely edit the primate genome at highly efficacious levels to significantly lower blood LDL cholesterol and triglycerides,” Dr Kathiresan said in his keynote address titled as “From reading the genome for risk to rewriting it for health” at the ISSCR annual meeting.
“The findings are very encouraging and add to our growing body of evidence in using both base editing and CRISPR-Cas9 in vivo against various gene targets. We expect to choose a lead programme by year-end 2020 with the goal of initiating human clinical studies within the next three years,” he added.
The next-gen cardiovascular medicine researcher conducted the gene-editing study in a total of 14 non-human primates and evaluated in vivo liver base editing to turn off 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.
Verve’s proprietary drug product consisting of the ABE mRNA and an optimized guide RNA packaged in an engineered lipid nanoparticle was delivered through a single intravenous infusion. Across two separate studies, seven animals were treated with the drug product targeting the PCSK9 gene and seven additional animals with the drug product targeting the ANGPTL3 gene.
One-time gene editing treatment
In the studies, the whole liver editing, blood protein and lipid levels were measured at two weeks and compared to baseline. The programme targeting PCSK9 showed an average of 67% whole liver PCSK9 editing, which translated into an 89% reduction in plasma PCSK9 protein and resulted in a 59% reduction in blood LDL cholesterol levels. The programme targeting ANGPTL3 showed an average of 60% whole liver ANGPTL3 editing, which translated into a 95% reduction in plasma ANGPTL3 protein and resulted in a 64% reduction in blood triglyceride levels and a 19% reduction in LDL cholesterol levels. In addition, in studies in primary human hepatocytes, clear evidence of on-target editing was observed with no evidence of off-target editing.
“These data are exciting and demonstrate our ability to turn off PCSK9 or ANGPTL3 in the liver to safely and effectively lower LDL cholesterol and triglyceride levels in non-human primate models using adenine base editing,” said Dr Andrew Bellinger, chief scientific officer of Verve Therapeutics.
“Very importantly, we do not find evidence of off-target editing using adenine base editing with carefully selected guide RNAs. These findings support Verve’s transformative
idea to develop once-and-done gene-editing treatments for adults with coronary heart disease and we look forward to presenting additional data in the future.”
Verve has built a portfolio of key gene editing and delivery technologies through established collaborations and license agreements with industry leaders. The company has license agreements with Harvard University and the Broad Institute of MIT and Harvard for foundational CRISPR patents, including Cas9 and Cas12a (Cpf1), for human therapeutic applications against certain other cardiovascular targets.