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Crispr Treatment Leads to Durable Cholesterol Reduction

Crispr graphic

(LJNovaScotia, Pixabay)

19 May 2021. A developer of gene editing for inherited heart disease reports lab monkeys given its therapy experience lower cholesterol levels for at least eight months. A team from Verve Therapeutics Inc., in Cambridge, Massachusetts with colleagues at University of Pennsylvania report the findings in today’s issue of the journal Nature (paid subscription required).

Verve Therapeutics is a two year-old biotechnology enterprise spun-off from Massachusetts General Hospital and the Broad Institute, a genetic research center affiliated with Harvard University and MIT, developing treatments for coronary artery disease, also known as atherosclerosis or hardening of the arteries. Coronary artery disease often results from a build-up of cholesterol and triglyceride plaques in the arteries feeding the heart, and is a major risk factor for heart attacks and other cardiac diseases.

Unlike most treatments that aim to reduce cholesterol or triglycerides already in the blood, Verve expects to identify people with higher genetic risk of coronary artery disease and edit the genes with mutations responsible for causing high plaque levels. Gene editing in this case, says Verve Therapeutics, needs to be very precise and granular, addressing pairs of nucleic acids called base-pairs that make up DNA.

Humans have about 3 billion pairs of nucleic acids — adenine (A) with thymine (T), and cytosine (C) with guanine (G) — with the sequence of these nucleic acid pairs comprising a person’s DNA or genetic code. When mutations or errors occur in the these nucleic acids, the errors are transcribed into faulty instructions provided to cells with RNA and the proteins that result from those instructions.

One-time treatment for a chronic disease

The company licenses its Crispr base-editing technology from Beam Therapeutics, also a spin-off company from Broad Institute in Cambridge; researchers from Beam took part in this study. Crispr, short for clustered regularly interspaced short palindromic repeats is a genome-editing process based on bacterial defense mechanisms that use RNA to identify and monitor precise locations in DNA. For coronary artery disease, the genome edits address genes producing proteins in the liver, including from the PCSK9 gene to regulate cholesterol in the blood stream. PCSK9 controls the number of receptors for low-density lipoproteins or LDLs, the so-called bad cholesterol, produced in the liver.

Verve’s lead product, code-named Verve-101, is designed to edit the PCSK9 gene and now in preclinical development. As reported by Science & Enterprise in June 2020, Verve Therapeutics presented findings from tests of its experimental therapy in lab monkeys that show monkeys receiving single infusions of the gene-edited treatment have lower levels of PCSK9 and a gene responsible for triglycerides in their blood, as well as reduced levels of LDLs and triglycerides.

The new paper presents results with longer-term effects of the gene editing therapy. The findings show monkeys receiving a single treatment experience 90 percent reductions in PCSK9 in the liver and 60 percent reductions in LDLs in their blood. Moreover, those lower PCSK9 and LDL levels remain stable for at least eight months, with later data showing the reductions continuing for up to 10 months. The data also show the monkeys, or non-human primates, largely tolerate the treatments, with low biomarker levels indicating liver damage and few off-target gene edits, in the spleen and adrenal glands.

Verve is developing Verve-101 initially as a one-time treatment for patients with heterozygous familial hypercholesterolemia,  or HeFH, a genetic heart disorder resulting in dangerously high levels of cholesterol, leading to heart failure, heart attack, or stroke at an early age. “Our goal is to disrupt the cardiovascular disease chronic care model,” says Verve co-founder and CEO Sekar Kathiresan in a company statement, “by providing a new therapeutic approach with single-course, in vivo liver-targeted gene editing treatments aimed at addressing the root causes of this highly prevalent and life-threatening disease.”

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