Gene Therapy for Heart Failure Demonstrates Safety and Efficacy in Phase 1 Trial

A phase 2 trial is being conducted after findings showed safety of the gene therapy product and stabilization or improvement in severity of patients’ condition at 12 months post-treatment.

Phase 1 data for a new gene therapy heart failure treatment demonstrates the drug’s safety in treating congestive heart failure with reduced left ventricular ejection fraction (LVEF), along with early signs of efficacy, according to new data published in Nature Medicine by investigators from Mass General Brigham.

Approximately 60 million people globally live with heart failure and about half have reduced LVEF, a condition in which the heart does not pump enough blood to meet the body’s needs and is linked to a higher risk of death. Despite existing therapies, the condition continues to be associated with a high mortality rate. Gene therapy, which works by modifying a patient’s genetic material at the cellular level, has the potential to be more effective than traditional drugs. In the current study, researchers used a new gene therapy that uses a modified virus to deliver treatment directly into the coronary arteries using a minimally invasive procedure.

“Within our heart failure patient population, we sometimes reach a point where, despite all standard-of-care interventions—whether pharmacologic or device-based—patients continue to worsen clinically,” said Roger J. Hajjar, MD, Director of the Gene and Cell Therapy Institute at Mass General Brigham. “These are exactly the individuals we aim to help with this new treatment.”

Investigators enrolled 11 patients from three centers with persistently severe symptoms from chronic non-ischemic cardiomyopathy (heart damage that is not caused by blocked arteries) and heart failure with reduced ejection fraction. Participants were sorted into two cohorts with cohort 1 receiving a higher dose and cohort 2 receiving a lower dose of a new gene therapy product (AB-1002) through a minimally invasive intracoronary infusion. All participants were monitored for 12 months following treatment. Afterward, they entered a long-term follow-up period, during which semi-structured phone questionnaires were conducted every six months for up to three years.

Among the patients enrolled, nine were male and two were female. The majority exhibited either stability or improvement in disease severity across both cohorts. Importantly, no adverse events attributable to the study treatment were noted, supporting the favorable safety profile of the therapy. Clinically significant improvements were documented through various efficacy assessments in participants with non-ischemic congestive heart failure. Additionally, the data indicate that a single intracoronary administration of the newly engineered AAV carrying the therapeutic gene shows strong selective targeting of cardiac cells.

This study is limited by its small sample size and its design as a single-arm, open-label, non-placebo-controlled phase 1 trial. Hajjar and colleagues are now conducting a phase 2 randomized, double-blind, placebo-controlled trial.

“It is highly gratifying to note that the foundational research and initial progress regarding the therapeutic target—a constitutively active form of protein phosphatase inhibitor 1—were accomplished in our laboratory at Mass General Brigham many years ago. Following clinical development, we are now witnessing its application for patients with urgent medical needs,” said Hajjar.

"The translation of this foundational work to patients through a First-in-Human trial exemplifies the core objective of the Mass General Brigham Gene and Cell Therapy Institute, which acts as a catalyst for advancing a range of basic research initiatives to clinical trials utilizing gene and cell therapy platforms," said Nathan Yozwiak, PhD, Head of Research at the Mass General Brigham Gene and Cell Therapy Institute.

Authorship: Additional authors include Timothy D. Henry, Eugene S. Chung, Monica Alvisi, Ferzin Sethna, David R. Murray, Jay H. Traverse, Lothar Roessig, Luke Roberts, Swarna Reddy, Youjun Chen, Tugba Guven Ozkan, Stacy Webb, Monika Mittal, Leigh Ervin, Hesham Sadek, Sheila Mikhail, Kobra Haghighi, Canwen Jiang, R. Jude Samulski, Evangelia G Kranias, Anna P. Tretiakova.

Disclosures: Hajjar is a consultant at AskBio; is a scientific cofounder of Nanocor, a subsidiary of AskBio; and holds a patent (20200054652) that has been licensed by Mass General Brigham to AskBio. Additional author disclosures can be found in the paper.

Funding: The clinical trial was funded by AskBio (Research Triangle Park, NC). AskBio was involved in the study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.

Paper cited: Henry, T. et al. “A First-in-Human, Phase 1, Open-Label, Dose-Escalation Study of AB-1002 for the Treatment of NYHA Class III Heart Failure” Nature Medicine DOI: 10.1038/s41591-025-04011-z