Dual-Action AAV Gene Therapy Restores Cardiac Function in Heart Failure Mouse Model

December 04, 2025— CINCINNATI, OH — Scientists at Cincinnati Children’s have reported a breakthrough in the development of a gene therapy for heart failure, a condition affecting millions of adults and up to 14,000 children annually in the U.S. The therapy, centered on the cardiac microprotein DWORF, successfully restored healthy cardiac function in a heart failure mouse model.

The findings, published in Circulation Research, demonstrate that DWORF, delivered via an AAV (adeno-associated virus) vector, offers a dual mechanism of action—correcting calcium cycling defects and boosting cellular energy supply—a benefit currently unavailable in existing heart failure treatments.

AAV Therapy Targets the Root of Cardiac Dysfunction

A core issue in many heart failure cases is the diminished function of the protein SERCA2a, a calcium pump essential for recharging the heart muscle’s energy supply during each beat. Early attempts to restore SERCA2a directly via gene therapy have faced challenges related to gene size and inefficient delivery.

The new approach utilizes DWORF, a microprotein co-discovered in 2016 by corresponding author Cat Makarewich, PhD.

“One of the core problems in heart failure is that heart muscle cells can’t handle calcium properly, which disrupts both the heart’s ability to contract and its cellular energy supply,” Dr. Makarewich said. “Our study shows that a newly discovered protein called DWORF, delivered through gene therapy, can fix both of these problems by restoring calcium balance and boosting mitochondrial energy production.”

DWORF is a much smaller protein than SERCA2a and works by activating the patient’s own SERCA2a pump while displacing its natural inhibitors.

MyoAAV Vector Delivers Dual Benefit

To test the therapeutic concept, researchers used a next-generation gene therapy vector, a myo-adeno-associated virus (MyoAAV), to overexpress DWORF in the hearts of mice.

The DWORF AAV gene therapy successfully delivered a dual mechanism of action:

1. Restored Calcium Cycling: DWORF directly activated the SERCA2a calcium pump, correcting the calcium handling defect.

2. Mitochondrial Boost: DWORF overexpression enhanced mitochondrial respiration and elevated the active levels of pyruvate dehydrogenase (PDH), a key enzyme for energy production within the heart muscle cells.

These changes led to significant functional benefits in a heart failure mouse model. The AAV-DWORF therapy preserved left ventricular function and reduced harmful cardiac remodeling, whether it was delivered preventively or after heart failure had already developed.

Researchers are now focused on optimizing the AAV dose, conducting safety studies in larger animals, and preparing for the regulatory steps necessary to advance this DWORF AAV gene therapy into human clinical trials.