What if a single injection could lower blood cholesterol and triglyceride levels for life?
In the first such gene-editing experiment, scientists have disabled two genes in monkeys that increase the risk of heart disease. Humans also carry genes, and the experiment has raised hopes that a leading assassin may one day be tamed.
“This could be the cure for heart disease,” said Dr. Michael Davidson, director of the University of Chicago Pritzker School of Medicine Lipid Clinic, 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 record. It is too early to know if the strategy will be safe and effective in humans; even monkeys must be monitored for side effects or other treatment failures for some time.
The results were presented Saturday at the annual meeting of the International Society for Stem Cell Research, held this year with virtually 3,700 attendees worldwide. Scientists are writing their findings, which have not yet been peer-reviewed or published.
The researchers set out to block two genes: PCSK9, which helps regulate LDL cholesterol levels; and ANGPTL3, part of the system that regulates triglycerides, a type of fat in the blood. Both genes are active in the liver, which is where cholesterol and triglycerides are produced. People who inherit mutations that destroyed gene function do not get heart disease.
People with elevated blood triglyceride and LDL cholesterol levels have dramatically increased risks of heart disease, heart attack, and stroke, the leading causes of death in most of the developed world. Pharmaceutical companies have already developed and are marketing two so-called PCSK9 inhibitors that markedly lower LDL cholesterol, but they are expensive and need to be injected every few weeks.
The Verve Therapeutics researchers, led by Dr. Sekar Kathiresan, the executive director, decided to edit the genes. The drug they developed consists of two pieces of RNA: a gene editor and a little guide that directs the editor to a single 23-letter sequence of human DNA among the 32.5 billion letters in the genome.
The RNA is wrapped in tiny lipid spheres to prevent the drug from instantly breaking down in the blood. The lipid spheres travel directly to the liver, where the liver cells ingest them. The contents of the spheres are released, and once the editor reaches his destination, he changes a single letter in the sequence to another, like a pencil that erases one letter and writes in another.
The researchers reported that the system not only worked on 13 monkeys, but it appeared that all of the liver cells were edited. After gene editing, the monkeys’ LDL levels dropped 59% in two weeks. Editing the ANGPTL3 gene led to a 64% decrease in triglyceride levels.
One danger of gene editing is that the process can result in DNA modification that scientists don’t expect. “It can never have off-target effects,” said Dr. Deepak Srivastava, president of the Gladstone Institutes in San Francisco.
By treating a condition as common as heart disease, he added, even a rare side effect can mean that many patients are affected. So far, however, researchers say they haven’t seen any inadvertent editing of other genes.
Another question is how long will the effect last on cholesterol and triglyceride levels, Davidson said. “We hope it will be only once, but we have to validate that with clinical trials,” he said.
Jennifer Doudna, a biochemist at the University of California, Berkeley, and discoverer of Crispr, the revolutionary gene-editing system, said: “In principle, Verve’s approach could be better because it is a unique treatment.”
But it is too early to say whether it will be safe and durable, he added.
If the strategy works in humans, its greatest impact may be in poorer countries that cannot afford expensive injections for people at high risk for heart disease, said Dr. Daniel Rader, chair of the genetics department at the University of Pennsylvania and a member . from the Verve Scientific Advisory Council.
Verve’s Kathiresan noted that half of the first heart attacks end in sudden death, so there is an imperative to protect high-risk people.
Kathiresan began the research at Massachusetts General Hospital and the Broad Institute, where he and his colleagues found a collection of genes that increase the risk of heart attack at a relatively young age, as well as eight genes that, when mutated, decrease the risk. .
Those protective genes, he reasoned, could be targets for gene editing if there was a way to alter them in people. Gene editing is only now being successful, and its successes so far have been in rare diseases.
Other researchers and companies have tried to edit genes in mice to prevent heart disease, with some success, but primates are a much more difficult challenge.
Kathiresan said that, to the best of his knowledge, his study is the first to use primate pencil and eraser gene editing for a very common disease. Verve licensed the technology, called the base edition, from Beam Therapeutics.
If all goes well, Kathiresan hopes in a few years to start treating people who have had heart attacks and who still have high and dangerous cholesterol. For them, the risk of another heart attack is so high that the possible benefit may far outweigh the risks of treatment.
Heart disease generally occurs only after decades of high cholesterol levels, Davidson noted. By age 50, people most likely to have a heart attack already have a significant buildup of plaque in their arteries.
But if the PCSK9 gene could be removed in people in their 20s, he said, “there would be no heart disease in their future.”