Muscle-targeted gene therapy for SLC25A4 mitochondrial deficiency

Unmet Need

There is a significant unmet need for disease-modifying therapies that address mitochondrial dysfunction in inherited cardiomyopathies and myopathies such as SLC25A4 deficiency. Existing treatments are limited to supportive care and heart transplantation, with no approved therapies that restore mitochondrial bioenergetics or halt progressive cardiac remodeling. Conventional AAV-based gene therapies face challenges with off-target liver uptake, reducing efficacy in muscle tissues—highlighting the need for delivery platforms that enhance cardiac and skeletal muscle targeting while minimizing hepatic exposure.

Technology

Duke inventors have developed an AAV-based gene therapy to treat SLC25A4 mitochondrial dysfunction in cardiac and skeletal muscle. This is intended to enhance myocyte bioenergetics, improve exercise capacity, and prevent disease progression, including myocardial thickening and heart failure, in patients with biallelic SLC25A4 mutations. Specifically, the platform employs a cross-species evolved, liver-detargeted AAV capsid (cc84) to deliver the SLC25A4 gene under the control of a cardiac- and muscle-specific promoter, enabling efficient expression in muscle cells while reducing biodistribution and expression in off-target organs such as the liver. Efficacy has been demonstrated in key, translationally relevant proof-of-concept studies, including patient-derived cardiomyocytes and an SLC25A4 knockout mouse model that recapitulates multiple hallmarks of human disease—such as cardiac remodeling, fibrosis, reduced contractile function, and elevated plasma alanine. Treatment of SLC25A4 knockout mice with a single systemic dose of AAV.cc84-SLC25A4 restored cardiac function, preserved exercise tolerance, reduced fibrosis, improved survival, and minimized off-target liver expression.

Other Applications

This platform could be extended to other mitochondrial transporter deficiencies or muscle-centric mitochondrial diseases requiring targeted gene replacement.

Advantages

• Enables targeted gene delivery to cardiac and skeletal muscle with reduced off-target liver expression.
• Demonstrates robust improvement in cardiac function, exercise capacity, and survival in preclinical models.
• Provides a durable, systemic therapy that addresses the underlying genetic cause of disease.