Boston-based Verve Therapeutics announced promising results from a Phase 1 trial of a novel gene-editing treatment that reduced dangerously high cholesterol levels by up to 55% in patients with familial hypercholesterolemia. The breakthrough, presented at the American Heart Association's November meeting, represents a potential paradigm shift in treating cardiovascular disease, which kills nearly 700,000 Americans annually and remains the nation's leading cause of death.
The trial enrolled 10 participants suffering from familial hypercholesterolemia, an inherited condition causing extremely high cholesterol that often leads to early death from cardiovascular disease. The treatment employs base editing, a precision gene-editing technique that makes targeted changes to a single base in a patient's DNA within liver cells.
Targeting the PCSK9 Gene
The therapy specifically modifies the PCSK9 gene, which plays a crucial role in cholesterol metabolism. As Dr. Michelle O'Donoghue, associate professor at Harvard Medical School and McGillycuddy-Logue Distinguished Chair in Cardiology at Brigham and Women's Hospital, explained, PCSK9 is "one of the more elegant stories of drug development."
The gene produces a protein that targets LDL receptors on liver cell surfaces for degradation. These receptors are essential for removing excess LDL cholesterol—the "bad cholesterol"—from the bloodstream. When PCSK9 levels are too high, fewer receptors remain available to clear cholesterol from circulation.
"There were individuals who carried a loss-of-function mutation for that PCSK9 protein," O'Donoghue noted. "They were found to have low rates of cardiovascular disease, and it does not appear to come at the price of other abnormalities."
Early Results and Safety Considerations
The initial study focused primarily on safety assessment, with most participants receiving doses too small to produce measurable cholesterol changes. However, three subjects who received higher doses experienced LDL reductions of more than 50%. The treatment is administered through IV infusion and theoretically could provide lifelong benefits from a single dose, though participants have only been followed for six months.
Two adverse events occurred during the trial—a heart attack and a fatal cardiac arrest—though investigators determined the treatment was likely not the cause. O'Donoghue emphasized that "these were very sick persons in the first place" and that "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."
Reversibility and Long-term Implications
Unlike traditional CRISPR gene editing, which permanently cuts both DNA strands, base editing offers potential reversibility. "The base editing used in this case holds the possibility of being reversible," O'Donoghue explained. "Some have used the analogy that it's more like a pencil and eraser than a pair of scissors. You're making a single base change on a strand of DNA to change the spelling, in essence, of that gene."
However, the permanent nature of DNA modification raises significant concerns. "For many of these gene-editing strategies, you are, in essence, permanently changing that person's DNA," O'Donoghue cautioned. "We need to follow people who are being treated with novel gene-editing therapies for several years before we can feel confident about recommending the therapies on a more widespread basis."
Regulatory Path Forward
The treatment faces years of additional clinical trials before potential FDA approval. The regulatory challenge is unique because, unlike traditional medications that can be discontinued, gene editing creates permanent changes. "We're talking about a permanent change to the DNA and these are relatively uncharted waters," O'Donoghue noted. "So how long you need to follow somebody to be confident about the safety profile will be a challenge for the FDA to determine."
Dr. Wesley Milks, a cardiologist at Ohio State University Wexner Medical Center, emphasized the scale of research still needed: "Many hundreds if not thousands of similar patients would need to be treated to show the safety and effectiveness of this therapy before the Food and Drug Administration or other international regulatory bodies would consider approval."
Broader Therapeutic Landscape
The development opens new possibilities for treating various cardiovascular conditions. O'Donoghue highlighted amyloidosis, a protein deposit condition affecting the heart, as another potential target where "few treatments exist." The approach may prove particularly valuable for rare genetic diseases where conventional therapies are unavailable.
Dr. Spencer Kroll from the Northeast Lipid Association described the research as "a groundbreaking change in the world of cardiovascular medicine," noting that it represents a shift "away from the one-size-fits-all statin treatment to therapies that are personalized to the individual patient."
While the treatment showed promise in reducing cholesterol levels significantly, O'Donoghue cautioned that patients wouldn't be "bulletproof when it comes to having a heart attack" since other pathways contribute to cardiovascular disease. The therapy represents what was once "thought of as science fiction making its way slowly into prime time," offering hope for patients with genetic predispositions to high cholesterol who don't respond adequately to current treatments.
