What if a single injection could lower blood levels of cholesterol and triglycerides — for a lifetime?
In the first gene-editing experiment of its kind, scientists have disabled two genes in monkeys that raise the risk for heart disease. Humans carry the genes as well, and the experiment has raised hopes that a leading killer may one day be tamed.
“This could be the cure for heart disease,” said Dr. Michael Davidson, director of the Lipid Clinic at the University of Chicago Pritzker School of Medicine, who was not involved in the research.
But it will be years before human trials can begin, and gene-editing technology so far has a mixed tracked record. It is much too early to know whether the strategy will be safe and effective in humans; even the monkeys must be monitored for side effects or other treatment failures for some time to come.
The researchers set out to block two genes: PCSK9, which helps regulate levels of LDL cholesterol; and ANGPTL3, part of the system regulating triglyceride, a type of blood fat. Both genes are active in the liver, which is where cholesterol and triglycerides are produced. People who inherit mutations that destroyed the genes’ function do not get heart disease.
People with increased blood levels of triglycerides and LDL cholesterol have greater risks of heart disease, heart attacks and strokes, the leading causes of death in most of the developed world. Drug companies already have developed two so-called PCSK9 inhibitors that lower LDL cholesterol, but they are expensive and must be injected every few weeks.
Researchers at Verve Therapeutics, led by Dr. Sekar Kathiresan, edited the genes instead. The medicine they developed consists of two pieces of RNA — a gene editor and a tiny guide that directs the editor to a single sequence of 23 letters of human DNA among the genome’s 32.5 billion letters.
The RNA is shrouded in lipid spheres to protect the medicine from being instantly degraded. The spheres travel to the liver where they are ingested by liver cells. The contents of the spheres are released, and once the editor lands on its target, it changes a single letter of the sequence to another.
Not only did the system work in 13 monkeys, the researchers reported, but it appeared that every liver cell was edited. After gene editing, the monkeys’ LDL levels dropped by 59% within two weeks. The ANGPTL3 gene editing led to a 64% decline in triglyceride levels.
The scientists’ findings have not yet been peer-reviewed or published.
One danger of gene editing is the process may result in unexpected modification of DNA. “You will never be able to have no off-target effects,” said Dr. Deepak Srivastava, president of the Gladstone Institutes in San Francisco.
In treating a condition as common as heart disease, he added, even an uncommon side effect can mean many patients are affected. So far, the researchers say they have not seen any inadvertent editing of other genes.
Another question is how long the effect will last, Davidson said. “We hope it will be one-and-done, but we have to validate that with clinical trials,” he said.