by Alvin Powell, Harvard Gazette

Credit: Harvard Gazette

A recent trial of a novel gene-editing technique that lowered dangerously high cholesterol by up to 55% has generated talk of a new front opening against cardiovascular disease, which kills nearly 700,000 Americans each year and is the nation's leading cause of death.

In a presentation at the American Heart Association's November meeting, Boston-based Verve Therapeutics announced results of a Phase 1 trial of 10 participants suffering from familial hypercholesterolemia, an inherited condition causing extremely high cholesterol, which often leads to early death due to cardiovascular disease.

The treatment uses a gene-editing technique called base editing, in which precision changes are made to a single base in a patient's DNA in the liver. In this case, the change was made to a gene that changed the liver's handling of LDL, popularly termed "bad cholesterol."

To learn more, the Gazette spoke with Michelle O'Donoghue, associate professor at Harvard Medical School and McGillycuddy-Logue Distinguished Chair in Cardiology at Brigham and Women's Hospital. O'Donoghue said the advance has generated extraordinary optimism in cardiology circles, tempered by caution due to the risks inherent in changing a patient's DNA.

GAZETTE: This was just an initial Phase 1 trial, but the results have generated a lot of excitement. How would you characterize the trial's outcome?

O'Donoghue: This was a radical concept developed inside a lab and to see it being translated into the treatment of real people is an extraordinary leap. There's a mix of enthusiasm and optimism for this novel technology, but also a healthy dose of caution and concern. We still need to completely understand the efficacy and safety profile of this type of approach.

There were two adverse events among the participants, a heart attack and a cardiac arrest—one of which was fatal. It was ultimately determined that the treatment was likely not the cause. But do these kinds of incidents reflect why there is so much concern over safety and efficacy?

It's more conceptual. There were too few patients within that initial cohort to really have a firm handle on the safety profile. As the investigators themselves stated, these were very sick persons in the first place. It makes sense to start the investigation of these therapies in patients who need it most desperately—they have genetic conditions that predispose them to very elevated cholesterol levels and already have established atherosclerotic disease (buildup of fatty plaque in the arteries). That being said, in the absence of a control group, one doesn't know whether or not the treatment was related to the occurrence of the heart attack or fatal cardiac arrest.

But I think that the concerns are more than just theoretical. For many of these gene-editing strategies, you are, in essence, permanently changing that person's DNA. There are different approaches, some of which are thought to be in part reversible, but nonetheless this type of strategy toward treating illness is going to come with some skepticism. And this early on, that is certainly appropriate.

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