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Trial Begins of Precise Gene Editing for Heart Disease

Heart and major blood vessels

(NIH.gov)

12 July 2022. A clinical trial is underway evaluating a precise form of Crispr gene editing as a one-time therapy for an inherited form of heart disease. The study is testing an experimental treatment developed by Verve Therapeutics Inc. in Cambridge, Massachusetts as a therapy for heterozygous familial hypercholesterolemia, or HeFH.

Verve Therapeutics is a four year-old enterprise creating treatments for inherited cardiovascular disorders beginning with HeFH. The company is spun off from labs at Mass. General Hospital in Boston and the Broad Institute, a genomics research center affiliated with MIT and Harvard University. The Verve technology applies base editing, a precise and granular form of Crispr, short for clustered, regularly interspaced short palindromic repeats, adapted from a bacterial process for protecting against attacks by viruses.

With base editing, Crispr is used to edit point mutations, errors in DNA where a single base pair is replaced by another base pair. The human genome consists of about three billion base pairs of nucleic acids: adenine (A) paired with thymine (T), and cytosine (C) with guanine (G). The sequence of those base pairs makes up an individual’s unique genetic code or DNA, with half or more of DNA errors made up of point mutations, linked to a range of diseases.

Edit gene to lower LDL cholesterol

HeFH is one of those diseases, a genetic heart condition that results in high levels of low-density lipoprotein or LDL cholesterol, the so-called bad cholesterol contributing to heart failure, heart attack, or stroke, often at an early age. Verve Therapeutics designed its lead product candidate, code-named Verve-101, to edit the PCSK9 gene that regulates receptor proteins for LDLs produced in the liver. Verve-101, says the company, sends nanoscale lipid particles with RNA to guide an enzyme to the PCSK9 gene that edits the base pairs in the gene to lower LDL cholesterol levels. In May 2021, Science & Enterprise reported on preclinical tests of Verve-101 in lab monkeys, showing lower cholesterol levels for at least eight months.

The early-stage clinical trial is enrolling 44 participants diagnosed with HeFH in Auckland and Christchurch, New Zealand. Verve Therapeutics says the first of those participants received an infusion of Verve-101. The study team first plans to give escalating doses of the treatment, watching for signs of adverse effects in the next year. Based on initial findings, researchers will then give a second dose of Verve-101, also looking for adverse effects, but as well for chemical concentrations and time of activity of the therapy in patients. In addition, the team is tracking PCSK9 concentrations in blood plasma and LDL cholesterol or LDL-C levels in recipients. The trial has no control or comparison group.

“With the current standard of care treatment for HeFH,” says Verve Therapeutics chief scientist Andrew Bellinger in a company statement, “less than 20 percent of patients achieve LDL-C goal levels due to the limitations of the chronic model which requires rigorous patient adherence, regular health care access, and extensive health care infrastructure. Verve-101 has the potential to change the way cardiovascular disease is cared for by lowering LDL-C as low as possible for as long as possible after a single treatment.”

The company plans to seek authorization from regulatory agencies for clinical trials of Verve-101 later this year in the U.K. and U.S.

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