Gene editing technologies that have revolutionized medicine since 2016 can also be used to treat common heart diseases, the number one cause of death in humans, according to a study recently published by one of the world’s leading scientists, Eric Olson, Ph.D. , from the United States. His team was able to modify two letters – or bases – of the roughly 3,000 million that make up a mouse’s DNA. This change was enough to silence a protein associated with multiple cardiovascular problems. Olson is cautious, but highlights the potential advantages of this new strategy: Because heart cells last a lifetime, it’s only a matter of making the change once.
DNA is like a recipe book for making proteins, little machines that take care of the main tasks in an organism: carrying oxygen through the blood, fighting viruses, and digesting food. This clue is written in four letters, repeated millions of times: ATGGCGAGTTGC … Each of these letters is the first of a chemical compound with different amounts of carbon, hydrogen, nitrogen and oxygen: adenine (C₅H₅N₅), cytosine (C₄H₅N₃O), guanine (C₅H₅N₅O) and thymine (C₅H₆N₂O₂) . Olson’s group used an “accurate stylus” to change the A to G several times; Now the recipe is no longer the same.
This pin-sharp pen dates back to 2003, when Spanish scientist Francis Mujica serendipitously discovered that some microbes from the Santa Pola salt flats in Alicante, Spain, used molecular scissors to identify invading viruses and cut their genetic material. Mojica, from the University of Alicante, called this mechanism CRISPR. Then, in 2012, French biochemist Emmanuel Charpentier and American chemist Jennifer Doudna observed that these microbial scissors could be used to modify the DNA of any organism, a discovery that earned them the Nobel Prize in Chemistry. Now, Eric Olson’s team has used one of the most refined versions of these CRISPR tools: the so-called base editors, invented in 2016 by American David Liu, a Harvard chemist considered one of the geniuses of modern science.
Liu himself praises the new trial, saying it’s a clever use of core editors that raises the possibility of not only treating certain types of heart disease, but also preventing their development, either spontaneously or after injury. Until now, primitive CRISPR technologies have focused on trying to correct specific mutations that cause rare diseases. The new study helps expand the therapeutic applications of essential editors beyond simply treating a single gene mutation. Details of the experiment have been published in the journal Science.
Eric Olson, of the University of Texas Southwestern Medical Center, spoke about his research to EL PAÍS via video conference from Dallas, Texas, accompanied by a Spanish colleague from his lab, biologist Xurde Menéndez Caravia, co-author of the new study, who explained that the results of the first proof-of-concept are promising. very. This technique appears to be safe in mice; Now, what comes next is an exploration of potential long-term effects.
The researchers modified the recipe for a protein called CaMKII delta, overactivation of which causes several cardiovascular problems such as arrhythmias, heart failure, or damage to the heart muscle after myocardial infarction. By changing two letters in the recipe, the resulting protein is not hyperactive. Olson’s team used this technique in mice with damaged hearts after a heart attack, a phenomenon known as ischemic reperfusion injury. Rodents’ organs have regained function after genetically modifying their cells. As a treatment targeting large populations, it would be revolutionary. We are talking about myocardial infarction: potentially millions of people can be treated with this technique, ”says Menendez-Caravia.
The US company Verve Therapeutics is already using a similar strategy to disable a gene linked to high levels of bad cholesterol. After getting promising results in monkeys, the company started a clinical trial with people in July. The difference, Olson explains, is that Verve Therapeutics uses core editors to turn off a gene completely, while his team uses them to subtly correct its function. David Liu himself founded a company, Beam Therapeutics, which, with primary editors, began a trial in November in patients with sickle cell anemia, a genetic disorder of red blood cells.
Olson is aware of the limitations of his studies. “Does it work in animals besides a mouse? We haven’t tested it, of course, in primates, or certainly not in a human. So we need to make sure it’s effective and safe. Also, I think the long-term effects of this treatment need to be investigated, because once it’s corrected, it’s Forever,” the scientist admits.
For geneticist Lluís Montoliu, of Spain’s National Center for Biotechnology, database editors are an amazing achievement. “It was a great idea that David Liu had in 2016, and in just six years, we’re already talking about applications in animals and even in humans,” he celebrates. Montolio points out that the Grammar Editors recently saved the life of Alyssa, a British girl who had a very aggressive leukemia and was treated with donor white blood cells that had been modified with the revolutionary micro-tipped pen.
David Liu’s lab is constantly improving its core editors and regularly comes out with new, more refined versions, Montolio says, so much so that geneticists around the world can hardly keep up. However, the Spanish scholar maintains that the technique is still not perfect and can produce some unwanted changes in the letters; This occurred in Erik Olson rats, although there appeared to be no adverse effects.
Cardiologist Javier Lemeres is also very careful. At his hospital, Val d’Ebron in Barcelona, Spain, they studied molecules that were able to reduce heart damage from ischemia and reperfusion in mice and even in pigs. “There was very positive data, but when these molecules were tested in humans, the results were not the same,” explains Limeris, MD, chair of the Department of Family Cardiology and Cardiac Genetics at the Spanish Society of Cardiology. However, the doctor also admits his enthusiasm: “Gene editing opens up a very wide range of possibilities. I think it is the third revolution in medicine, after surgery and drugs.”