TAFAZZIN gene replacement therapy

Background

Barth Syndrome (BTHS) is an X-linked, potentially lethal genetic disease that affects about 1 in 0.3 to 0.4 million live births. It is characterized by cardiomyopathy, skeletal myopathy, neutropenia, growth delay, poor feeding, and organic aciduria, with cardiac complications and neutropenia being the leading causes of mortality. Over 70% of BTHS patients develop cardiomyopathy within their first year, and 14% of BTHS patients eventually require heart transplantation. The skeletal myopathy further leads to debilitating fatigue, significantly impairing daily activities and quality of life.

Current treatment relies solely on supportive medical management for cardiomyopathy, including standard heart failure medications, heart transplantation, and granulocyte-macrophage colony-stimulating factor (GM-CSF) for neutropenia. However, these approaches do not address the underlying cause of the disease, leaving a critical unmet need for targeted therapies that can provide more effective and lasting solutions for BTHS patients.

Technology Overview

Barth Syndrome (BTHS) is caused by mutations in the Tafazzin (TAFAZZIN) gene, which disrupt the biogenesis of cardiolipin (CL), a crucial mitochondrial phospholipid essential for energy production and cellular integrity. These mutations result in reduced levels of mature CL, accumulation of dysfunctional monolysocardiolipin (MLCL), impaired electron transport, increased reactive oxygen species (ROS), and inefficient ATP synthesis. Collectively, these mitochondrial defects drive the hallmark symptoms of BTHS.

Dr. William Pu’s team at Boston Children’s Hospital, in collaboration with the Barth Syndrome Foundation, developed an AAV-based TAFAZZIN gene therapy. They first characterized TAZ germline and conditional knockout mice, which recapitulate the major cardiac and skeletal muscle phenotypes of human BTHS. In these models, AAV-mediated TAFAZZIN gene replacement rescued neonatal survival, prevented cardiomyopathy, and reversed established cardiac disease. The research further underscored the importance of achieving sufficient cardiomyocyte transduction to ensure durable efficacy, highlighting the need for optimized cardiac delivery. Dr. Pu’s team also developed human iPSC-CM models of BTHS and demonstrated phenotypic rescue by TAFAZZIN gene replacement. The team has subsequently optimized the design of a clinical candidate AAV gene therapy vector to improve efficacy, specificity, and safety.

Compared to current supportive care options, this gene therapy represents a transformative, disease-modifying approach by targeting the root cause of BTHS rather than merely managing symptoms, setting a new standard for BTHS therapy.

Applications

• Treatment of Barth Syndrome (BTHS)

Advantages

• Curative: targets the root cause, not just symptoms.
• Cost-effective: potentially reduces long-term healthcare costs.
• Broad applicability: effective across disease stages, even in advanced stages.

Publications

Wang S, Li Y, Xu Y, et al. AAV Gene Therapy Prevents and Reverses Heart Failure in a Murine Knockout Model of Barth Syndrome. Circ Res. 2020;126(8):1024-1039. doi:10.1161/CIRCRESAHA.119.315956