Gene therapy for cardiovascular disease

Over the past decade, the Nobel prize-winning technology known as CRISPR has transformed biomedical research, enabling scientists to edit DNA far more easily and precisely than ever before. In late 2023, the first medical use of the gene editing tool was approved to treat sickle cell disease, an inherited blood disorder that causes excruciating pain, organ damage, and strokes.

Investigators are also using gene editing to develop novel therapies for several types of heart disease. Clinical trials are currently under way among people with three genetic conditions: abnormally high cholesterol; a type of heart muscle disease; and a form of heart failure that results from amyloid deposits. Preliminary results in small numbers of people appear promising.

However, there are still some considerable challenges related to developing and delivering gene therapy for heart disease, says Dr. Calum MacRae, vice chair for scientific innovation in the Department of Medicine at Harvard-affiliated Brigham and Women's Hospital. "Sickle cell disease results from a single, specific genetic defect. Most cardiovascular genetic disorders are caused by different genetic defects in each family, and the factors leading to clinical disease are less well known," he says. Gene variants can also have complex effects throughout the entire body, and editing the defect in single tissues may have unpredictable effects, he adds. Delivering the ideal "dose" of gene editing technology to the right types of cells may be an issue. There are also concerns about off-target effects elsewhere in the genome, as well as possible inflammatory reactions to the viruses or lipid particles used deliver the therapies.

Here's a brief summary of current gene therapies for heart disease.

Familial hypercholesterolemia (FH). About one in 250 people has a variant in the PCSK9 gene that causes extremely high levels of harmful LDL cholesterol. FH is one of the leading causes of premature heart attacks (those that occur before age 45 in men and 55 in women). A new gene editing therapy essentially turns off the PCSK9 gene in the liver. Early data found that a single infusion led to drops of 39% to 55% in LDL cholesterol. The nine adults who received the therapy (all of whom had one FH variant) had cardiovascular disease and high LDL, despite taking maximum doses of cholesterol-lowering drugs. The company continues to enroll people for the study, all of whom will be followed for another 14 years, which the FDA requires for all participants in any human genome editing trials.

Hypertrophic cardiomyopathy (HCM). An estimated one in 500 people have HCM, which results from variants in genes that affect the structure of the heart's muscle. More than a dozen genes have been linked to HCM, but the disorder is most often connected to variants in the myosin binding protein 3 (MYBPC3) gene. In people with these variants, the heart's walls may become abnormally thick, restricting blood flow and leaving the heart prone to dangerous, potentially fatal heart rhythms. A gene therapy trial that uses a virus to deliver a working copy of the MYBPC3 gene to the heart muscle began in the fall of 2023. Researchers plan to enroll at least six people with this particular gene defect who have symptoms of HCM (which include chest pain, fatigue, and shortness of breath) and who have implanted cardiac defibrillators.

Transthyretin amyloid cardiomy­opathy (ATTR-CM). The exact prevalence of this rare disorder is unclear because it is difficult to diagnose, but an estimated 5,000 to 7,000 new cases are identified in the United States each year. It occurs when a gene variant causes the liver to make an abnormal form of transthyretin (TTR) protein. Clumps of TTR build up, causing the heart's left ventricle to stiffen and weaken, potentially leading to heart failure. A trial using gene editing to stop the production of the abnormal TTR protein showed dramatic drops in the protein among the 60 people who received the therapy.

The big picture

The above conditions can all be treated with existing medications or procedures. The overarching problem is that they're usually discovered only at very advanced stages, after a person has developed severe symptoms. "The biggest unmet need in cardiovascular genetic disorders is identifying people when early, preventive interventions are feasible. Currently, most of these cases go undetected," says Dr. MacRae.

Still, gene therapy trials should radically improve recognition of these inherited heart diseases. "As we expand our detection of disease and the underlying gene defects, we will begin to better understand how these conditions affect patients, and how therapies of differing risk and benefit can best be implemented," says Dr. MacRae.