AAV Gene Therapy Using AAV-Ant1 Successfully Restores Mitochondrial Function to Halt Dilated Cardiomyopathy in Mouse Models

December 16, 2025 — A significant advance in cardiovascular medicine has been reported by a research team led by Angelin, Keller, and Lu, demonstrating that a targeted AAV (adeno-associated virus) gene therapy can partially restore mitochondrial function and protect against dilated cardiomyopathy (DCM) in genetically compromised mice. The findings, published in Nature Communications, pioneer a potential AAV therapeutic approach for human heart failure linked to mitochondrial dysfunction.

The heart is an extremely metabolically demanding organ, relying heavily on mitochondria for energy (ATP) production. Dysfunction of these organelles is a central cause of many heart diseases, including DCM, a condition marked by ventricular dilation and impaired function.

Targeting the Core Defect with AAV-Ant1

The study focused on ANT1 (adenine nucleotide translocator 1), a crucial protein embedded in the inner mitochondrial membrane that manages the critical exchange of ADP and ATP. Deficiencies in ANT1 are known to be associated with severe cardiomyopathies.

Researchers engineered a robust mouse model that lacked Ant1 (Ant1 -/-) and carried pathological mitochondrial DNA (mtDNA) mutations, mimicking complex human mitochondrial diseases. These mice developed severe mitochondrial dysfunction and progressive ventricular dilation typical of DCM.

The therapeutic strategy centered on using an AAV vector to deliver a functional copy of the Ant1 gene directly to the heart:

• AAV Delivery: A functional Ant1 gene was packaged into an AAV vector. AAV vectors are recognized as safe and efficacious gene delivery vehicles, capable of long-term transgene expression in post-mitotic tissues like the heart.

• Targeting: Systemic administration via tail vein injection allowed the AAV-Ant1 to achieve highly efficient cardiac-targeted transduction, ensuring the necessary ANT1 protein was expressed within the mitochondrial membranes.

Functional and Molecular Rescue by AAV Gene Therapy

Following treatment with the AAV-Ant1 gene therapy, the mouse models exhibited critical improvements, underscoring the potential of this AAV strategy:

• Mitochondrial Function: Measured improvements included enhanced ATP synthesis rates and a reduction in oxidative stress markers.

• Cardiac Function: Echocardiographic assessment showed the attenuation of ventricular dilation and a preservation of ejection fraction when compared to untreated controls.

• Mechanistic Insight: Re-expression of ANT1 restored mitochondrial bioenergetics by rebalancing the import/export of ADP/ATP, thereby supporting the high metabolic demands of cardiomyocytes. Intriguingly, the AAV treatment also appeared to normalize mitochondrial quality control processes, including a reduction in aberrant mitochondrial fission and defective mitophagy (clearance of damaged mitochondria).

This groundbreaking work validates the therapeutic viability of restoring ANT1 function using AAV gene therapy and provides strong preclinical evidence that this approach could interrupt the pathologic cascade leading to heart failure in mitochondrial cardiomyopathies.