(NIH.gov)
29 June 2020. An experimental therapy using a precise gene editing technique is shown in lab monkeys to reverse the cause of a chronic form of heart disease. Sekar Kathiresan, co-founder and CEO of Verve Therapeutics in Cambridge, Massachusetts presented the findings on Saturday at a virtual meeting of International Society for Stem Cell Research or ISSCR.
Verve Therapeutics is a one year-old spin-off enterprise 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 on 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 plans 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.
Verve licenses its Crispr base-editing technology from Beam Therapeutics, also a spin-off company from Broad Institute in Cambridge. 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 a pair of genes producing proteins in the liver: the PCSK9 gene to regulate cholesterol and ANGPTL3 regulating triglycerides 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, while the ANGPTL3 gene regulates lipid and glucose metabolism that can stimulate triglycerides.
At a plenary session of the ISSCR meeting, Kathiresan described adenine base editing to deliver single infusions of edited PCSK9 or ANGPTL3 genes in lipid nanoscale particles to 14 lab monkeys, with seven monkeys each receiving either edited PCSK9 or ANGPTL3 genes. The company reports monkeys receiving edited PCSK9 genes have 89 percent lower PCSK9 proteins in their blood, as well as 59 percent lower LDL cholesterol levels than before receiving the edited genes. Likewise, monkeys receiving edited ANGPTL3 genes have 95 percent lower levels of ANGPTL3 proteins, with 64 percent fewer blood triglycerides and 19 percent lower LDL cholesterol levels.
In addition, the study team found no evidence of off-target edits. “These proof-of-concept data,” says Kathiresan in a company statement, “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.”
Verve says it plans to decide on a lead product by the end of 2020, and begin clinical trials within three years.
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