Cleveland Clinic Researchers Reveal Initial Results from First-in-Human Gene Therapy for Hypertrophic Cardiomyopathy

Results from the first trial in humans using gene therapy for a specific type of heart disease – MYBPC3-related hypertrophic cardiomyopathy – show that the treatment is safe and increases levels of a key heart protein that may help improve heart structure and function. While promising, researchers caution that further research is needed.

Findings from the “MyPeak-1 Phase 1b/2 clinical trial” were presented today during a late-breaking science session at the American Heart Association’s Scientific Sessions 2025 in New Orleans. It was simultaneously published online in Cardiovascular Research.

Six adult patients were part of this first phase – three received a lower dose of the one-time infusion treatment called TN-201, which is a first-in-class adeno-associated virus-based gene therapy, while three received a higher dose. They were monitored between several months to more than a year. At the time of enrollment, all of the patients had significantly enlarged hearts despite prior interventions.

The findings show the treatment was mostly safe, with mild, temporary side effects that were quickly managed. Two patients experienced lab abnormalities that were monitored in hospital and resolved without causing symptoms. Immune suppressing drugs, which were administered to prevent an immune reaction to the treatment were all successfully tapered months after the dosing. Cardiac testing showed the treatment reached the heart cells and worked as intended, increasing the target protein levels and thinning the heart wall.

“These initial results are promising for a patient population that is too often misdiagnosed and live with difficult, even dangerous, symptoms,” said Milind Desai, M.D., M.B.A., director of the Hypertrophic Cardiomyopathy Center at Cleveland Clinic and vice chair of Cleveland Clinic’s Heart, Vascular & Thoracic Institute. Dr. Desai is an investigator for the MyPeak-1 Phase 1b/2 clinical trial. “In the past decade, we've made great progress in understanding and treating hypertrophic cardiomyopathy, and we're pleased to be potentially advancing it further as we continue to research this gene therapy.”

Myosin binding protein C3 (MYBPC3) gene mutations are the most common genetic cause of hypertrophic cardiomyopathy, which is a complex type of heart disease that causes thickening of the heart muscle, left ventricular stiffness and mitral valve changes. It affects an estimated 600,000 to 1.5 million Americans, or one in 500 people, but many of those patients go undiagnosed until the disease has progressed.

Symptoms of hypertrophic cardiomyopathy include chest pain, palpitations, shortness of breath, fatigue, and syncope (fainting). Most people with hypertrophic cardiomyopathy have a low risk for sudden cardiac death. However, the condition is the most common cause of sudden cardiac death in people under age 30.

There is currently only one disease-specific medication to treat hypertrophic cardiomyopathy. Mavacamten, a medication that was approved by the FDA in April 2022, following a trial led by Cleveland Clinic, is used to treat the obstructive form of hypertrophic cardiomyopathy and reduce the need for invasive procedures.

A majority of people with MYBPC3-associated HCM have the nonobstructive form of disease for which there are no disease-specific treatments. The MyPeak-1 Phase 1b/2 clinical trial is a multi-center study designed to assess the safety and clinical efficacy of a one-time infusion of TN-201.

The trial is sponsored by Tenaya Therapeutics Inc.

Dr. Desai is a paid consultant for Tenaya Therapeutics Inc., and Bristol Myers Squibb.