Roger Hajjar, MD, has spent decades trying to deliver gene therapies to the heart in hopes of treating patients with severe heart failure, a condition with few treatment options—one of which, heart transplantation, is far from simple. Hajjar’s early work at Massachusetts General Brigham (MGB), which began in 1997, focused on understanding the molecular underpinnings of heart failure and identifying proteins and pathways within cardiac cells that could be targeted therapeutically. Many of his patients had exhausted all available treatments, which pushed him to explore the potential of gene therapy.

“Cardiac gene therapy has been trialed in heart failure for many years,” Hajjar told Inside Precision Medicine. “Our lab started the first trial, called the CUPID trial, back in 2007. It was quite ambitious at the time. We were using primitive tools, if you want to call them that—but the field has evolved enormously since then.”

That promise may finally be taking shape. In a study published recently in Nature Medicine, researchers report results from the first-in-human trial of a novel adeno-associated virus (AAV) vector engineered to specifically target the heart—showing both safety and early signs of efficacy in patients with heart failure. The Phase I trial, led by Hajjar—now director of the Gene and Cell Therapy Institute at MGB—represents a major evolution from earlier attempts to deliver genes to cardiac tissue.

Precision targeting with cardiotropic vectors

The modern era of gene therapy has been driven by AAV vectors—small, nonpathogenic viruses that can carry therapeutic DNA into human cells. While AAV-based treatments have achieved striking successes in the eye, liver, and nervous system, the heart has remained a much tougher target.

The first cardiac gene therapy trials, including Hajjar’s aforementioned CUPID program nearly two decades ago, attempted to deliver the SERCA2a gene—encoding a key calcium pump in heart muscle cells—using early-generation AAV vectors. Those studies demonstrated proof of biological activity but failed to meet clinical endpoints in later stages, largely because the viral vectors were not sufficiently efficient or specific to cardiac tissue.

Since then, AAV vector engineering has undergone a revolution. Researchers have retooled the viral capsid—the protein shell that determines which tissues the virus infects—to enhance “tropism,” or tissue specificity. For cardiac applications, this meant finding capsid variants that preferentially target heart cells while avoiding off-target organs such as the liver.

The vector used in the new study, AB-1002, is a chimeric cardiotropic AAV originally developed by gene therapy pioneer R. Jude Samulski, PhD, a scientific founder of AskBio, and optimized by Hajjar’s team for cardiac delivery. AB-1002 delivers a gene encoding a constitutively active inhibitor of protein phosphatase 1 (I-1c)—a key regulator of calcium cycling and contractility in heart muscle cells. By blocking phosphatase 1 activity, I-1c helps sustain phosphorylation of proteins involved in calcium handling, thereby improving cardiac performance.

Unlike most systemic AAV gene therapies, which require high doses and immunosuppressive drugs, AB-1002 is infused directly into the coronary arteries via a standard cardiac catheterization procedure. “Because the doses are quite low and the delivery is local, there’s no need for immunosuppression,” Hajjar explained. “It’s performed through a standard cardiac catheterization—just like when we do angiography or place a stent.”

First-in-human results

In the open-label Phase I trial, 11 patients (nine men and two women) with nonischemic cardiomyopathy, New York Heart Association (NYHA) class III heart failure, and left ventricular ejection fractions (LVEF) between 15% and 35% received a single intracoronary infusion of AB-1002.

Patients were divided into two dose cohorts—six patients received a “low” dose (3.25×10¹³ viral genomes) and five patients received a “high” dose (1.08×10¹⁴ viral genomes). The therapy was well tolerated at both doses, with no serious adverse events attributed to treatment. Most adverse events were mild or moderate, and while one patient died during the study, investigators determined it was unrelated to the therapy. Mild, self-limiting increases in liver enzyme levels were observed, mainly in the higher-dose group.

Preliminary signs of efficacy were also encouraging. Patients in both cohorts showed improvements in NYHA class and LVEF, and the lower-dose group demonstrated gains in peak oxygen consumption and 6-minute walk distance—key indicators of cardiac function and endurance. In one patient who underwent a myocardial biopsy, researchers observed strong vector uptake throughout the heart muscle.

“These findings are the first clear signal that a cardiotropic vector can safely and effectively deliver a therapeutic gene to human heart tissue,” Hajjar said. “It’s incredibly gratifying to see this finally reach patients.”

Precision cardiology’s launch point

The development of AB-1002 and its translation to the clinic have taken over a decade, reflecting both the complexity of cardiac gene therapy and the persistence of the teams involved. A Phase II trial is already underway, enrolling 150 patients across multiple centers. “We’re about two-thirds through enrollment,” Hajjar said. “We expect to finish by early next year and see results about a year after the last patient is dosed.”

At MGB’s Gene and Cell Therapy Institute, Hajjar says the goal is to compress the timeline from discovery to clinical testing. “We can now produce vectors faster, clarify regulatory pathways, and reach patients much more efficiently,” he said.

The growing momentum across genetic medicine—from CRISPR-based cures for monogenic diseases to pathway-targeting therapies like this one—marks a broader shift in how researchers are approaching complex conditions. “We’ve seen what’s possible with gene editing, like in the case of Baby KJ,” Hajjar added. “That same energy is coming into all areas of genetic medicine, including cardiovascular disease. It’s a very exciting time.”

While the ultimate clinical impact will hinge on the ongoing Phase II results, the Nature Medicine report marks a pivotal milestone in the long quest to bring gene therapy to the heart. For a field that has often watched success stories unfold in other organs, the emergence of a truly cardiotropic vector may finally put cardiac gene therapy on the map.