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DWORF Gene Therapy Improves Cardiac Calcium Handling and Mitochondrial Function
Omar Brito-Estrada1,2,3, Yasuhide Kuwabara1,4, Aaron M Gibson1
1Division of Molecular Cardiovascular Biology, The Heart Institute (O.B.-E., Y.K., A.M.G., K.R.H., M.L.K., J.P.V., N.S.B., J.H., J.D.M., C.A.M.), Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
Circulation Research
|September 5, 2025
Summary
Overexpressing the cardiac microprotein DWORF improves calcium handling and mitochondrial function, offering protection against heart failure progression. This gene therapy shows promise for treating heart failure by enhancing cardiac energetics and reducing pathological remodeling.
Area of Science:
- Cardiology
- Molecular Biology
- Mitochondrial Physiology
Background:
- Calcium (Ca2+) dysregulation is central to heart failure, impairing cardiac function and remodeling.
- The sarcoplasmic reticulum Ca2+ ATPase isoform 2a (SERCA2a) activity decreases in heart failure.
- The cardiac microprotein DWORF enhances SERCA2a activity, improving cardiomyocyte calcium cycling.
Purpose of the Study:
- To investigate if DWORF overexpression improves SR Ca2+ handling and mitochondrial Ca2+ signaling.
- To determine if DWORF protects against pressure overload-induced heart failure.
- To assess DWORF's impact on cardiac function, metabolism, and remodeling.
Main Methods:
- Overexpression of DWORF in the heart using transgenic mice and adeno-associated virus (AAV) vectors.
- Induction of heart failure via transverse aortic constriction (TAC) in mice.
- Assessment of cardiac function, mitochondrial respiration, Ca2+ uptake, and pathological remodeling.
Main Results:
- DWORF overexpression enhanced mitochondrial respiration and Ca2+ uptake kinetics.
- Elevated levels of active pyruvate dehydrogenase (PDH) and mitochondrial Ca2+ uniporter were observed.
- AAV-mediated DWORF delivery protected against TAC-induced cardiac dysfunction and attenuated remodeling.
- Benefits were observed with both preventive and established heart failure treatment paradigms.
Conclusions:
- DWORF enhances SR Ca2+ dynamics and mitochondrial energetics.
- DWORF overexpression attenuates pathological remodeling and heart failure progression.
- DWORF represents a promising therapeutic target for heart failure treatment.
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