2020-06-30| In-DepthR&DTechnology

Verve Therapeutic’s One Time Base Editing Treatment Cuts Down Cholesterol Levels in Blood

by Ruchi Jhonsa
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By Ruchi Jhonsa, Ph.D.

At the International Society for Stem Cell Research (ISSCR) 2020 virtual annual meeting, the “next-generation cardiovascular company” presented a potential one-time solution to the maladies of coronary heart disease.

The rate of heart diseases has steadily surged, owing to sedentary lifestyles that have replaced physical activity and junk foods that have substituted healthy diets. Coronary artery disease is a common heart disease that takes millions of lives each year and is spiraling at a rapid rate. It is formed by the build-up of cholesterol and fatty deposit patches (plaques) that eventually blocks the arteries. Conventionally, coronary blockages are managed by blood thinners or cholesterol-reducing statins to keep blood pressure in check. However, health improvements are minimal due to poor adherence, high cost, drug-related side effects, and limited access to oral medications, especially in developing countries.


Base Editing to the Rescue

Cambridge, MA-based Verve Therapeutics is planning to overcome coronary blockage by permanently turning off the genes that increase cholesterol in the liver by using base editing. The gene-editing technology is similar to CRISPR with respect to finding the mutant stretch of DNA using Cas9 proteins. Yet, unlike the former, which resorts to double-stranded breaks to fix mutations, base editing just changes one DNA letter without affecting the bases around it. This reduces the infamous off-target effects generated by the classic CRISPR tool.

“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 U.S. and worldwide,” said Dr. Sekar Kathiresan, M.D., Co-founder, and CEO of Verve Therapeutics.

Verve is using the base editing technology on two protein targets, PCSK9 and ANGPTL3, both of which elevate bad cholesterol and triglyceride-rich lipoprotein in the blood. In 2006, scientists found out that deleting a single copy of PCSK9 can bring down blood cholesterol levels by 28% and reduce the risk of coronary artery disease by 88%. Similarly, deleting ANGPTL3 is beneficial for patients at the risk of coronary blocks as it reduces the risk of heart attack by 34%.


Base Editor’s Success Story

The two-part technology consists of mRNA that codes for base editor protein and a guide RNA that directs the base editor to the desired location. In contrast to traditional CRISPR treatments that package the editing machinery into a virus, Verve is using lipid-bound particles for its base editor’s delivery to the liver cells.

The company tested this drug on 14 cynomolgus monkeys. Half of the animals were injected with the PCSK9 base editors and the other half with ANGPTL3 editor. At two weeks following the drug treatment, 67% of the PCSK9 gene was switched off in the whole liver resulting in an 89% reduction in plasma PCSK9 levels and a 59% reduction in blood’s bad cholesterol levels. Concurrently, the ANGPTL3 targeting drug could lower down plasma ANGPTL3 protein levels by 95% and blood triglyceride levels by 64%. Although the scientists did not look for off-target effects in non-human primate liver cells, they observed no signs of it on primary human hepatocytes.

“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 Andrew Bellinger, M.D., Ph.D., CSO 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.


Human Trials on the Horizon

With positive results in the non-primate study, Verve is now eyeing for human trials in 2022 or 2023. Meanwhile, it is gathering all the resources it will need to build the gene-editing machinery. Verve is already in collaboration with Beam Therapeutics for its base editor for certain cardiovascular targets for which it holds an exclusive license. Additionally, it has made pacts with Harvard University and the Broad Institute of MIT and Harvard for Cas proteins, including Cas9 and Cas12a, for human therapeutic applications against certain cardiovascular targets. Once the preclinical studies are done, the company will pick a lead candidate and file an IND application with the FDA.

“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 program by year-end 2020 with the goal of initiating human clinical studies within the next three years,” said Dr. Kathiresan.

Editor: Rajaneesh K. Gopinath, Ph.D.

Related Article: FDA Approval of Cholesterol-Lowering Drug, NEXLETOL, A Value-Add to Existing Treatments



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