CRISPR Treatment Cuts Cholesterol by Up to 57% in a Single Shot

Scientists have improved upon a form of gene-editing therapy, creating an experimental treatment that looks to hold great promise for treating high cholesterol – a diagnosis affecting tens of millions of Americans, and linked to a number serious health complications. In new research conducted with mice, researchers used an injection of a newly-formulated lipid nanoparticle to deliver CRISPR-Cas9 genome editing components to living animals, with a single shot of the treatment reducing levels of low-density lipoprotein (LDL) cholesterol by up to 56.8 percent. In contrast, an existing FDA-approved lipid nanoparticle (or LNP; a tiny, biodegradable fat capsule) delivery system could only manage to reduce LDLs by 15.7 percent in testing. Of course, these results have so far only been demonstrated in mice, so the new therapy will take a lot of further testing before we know it’s both safe and equally effective in humans. But based on these results so far, signs are promising.

The way the treatment works relates to a gene in humans called Angiopoietin-like 3 (Angptl3), which produces proteins that inhibit the breakdown of certain fats in the bloodstream. People with a mutation in this gene tend to have lower amounts of fatty triglycerides and cholesterol in their blood – without showing other kinds of health complications – and for years scientists have been trying to recreate the process, with treatments that effectively mimic the effects of the mutation.

If we can replicate that condition by knocking out the Angptl3 gene in others, we have a good chance of having a safe and long term solution to high cholesterol,” says biomedical engineer Qiaobing Xu from Tufts University. “We just have to make sure we deliver the gene editing package specifically to the liver so as not to create unwanted side effects.

In the new research, Xu’s team developed a new formulation of LNPs called 306-O12B to target the gene, producing therapeutic effects in wild-type C57BL/6 mice that lasted at stable levels for 100 days after just a single injection of the treatment.

In addition to the cholesterol reduction, the experiment produced a 29.4 percent decrease in triglycerides in the animals’ blood, whereas the FDA-approved delivery method showed only a 16.3 percent reduction.

The findings are reported in PNAS.

How To Substantially Lower LDL Cholesterol Levels

Verve Therapeutics, a next-generation cardiovascular company, today announced the presentation of new preclinical proof-of-concept data in non-human primates that demonstrate the 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 is developing one-time gene editing medicines 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. The data were presented at the International Society for Stem Cell Research (ISSCR) 2020 Virtual Annual Meeting.

In a keynote address titled, “From reading the genome for risk to rewriting it for health,” Sekar Kathiresan, M.D., co-founder and chief executive officer of Verve Therapeutics, presented the results of recent studies utilizing adenine base editing (ABE) technology, licensed from Beam Therapeutics, in which substantial lowering of plasma LDL cholesterol or triglycerides was successfully 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.

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. Kathiresan. “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. 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.”

The studies were conducted 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.

Whole liver editing, blood protein and lipid levels were measured at two weeks and compared to baseline. The program 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 program 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 19% reduction in LDL cholesterol levels.

Source: https://www.vervetx.com/