From Molecular Mechanism to Therapy for Barth Syndrome
Abstract
Barth syndrome is a genetic disease that causes weakness of the heart and skeletal muscles, so that many patients suffer from debilitating fatigue and some require a heart transplant. There is currently no targeted treatment for Barth syndrome. Barth syndrome is caused by mutations in one gene, Tafazzin (TAZ). The exact ways that mutations in TAZ lead to muscle weakness remain incompletely understood, although at least one important way is by preventing the normal processing of an important mitochondrial lipid named cardiolipin. As a result, mitochondria, which are central to cell energy production and metabolism, do not work properly. Different Barth syndrome patients have wide variations in disease manifestations and severity. We have found that mice with loss of TAZ also have wide variation in disease manifestations and severity, and these differences are not associated with the severity of cardiolipin abnormalities. We have also shown that delivery of the normal TAZ gene to cells using a viral vector (“viral gene therapy”) was effective in correcting heart muscle disease in a mouse model of Barth syndrome. However, viral gene therapy was less effective for skeletal muscle disease, at least in part due to loss of the viral vector from skeletal muscle during postnatal growth and homeostasis. Here we propose to improve understanding and treatment of Barth syndrome. First, we will perform experiments designed to reveal genetic factors that modulate the manifestations and severity of TAZ mutation by performing genetic studies in TAZ mutant mice. Understanding genetic factors that protect some individuals from severe disease manifestations may lead to new methods to treat the disease in more severely affected individuals. Second, we will investigate the molecular machines that contain TAZ. Identifying these machines and understanding what they do will yield new insights into the function of TAZ. Third, we will develop a new gene therapy strategy designed to avoid loss of the viral vector. This strategy would permit durable gene therapy in skeletal muscle and enable gene therapy to be delivered in infancy. This proposal is relevant to PRMRP Topic Area of Congenital Heart Disease, since it will develop a new treatment for a form of cardiomyopathy (heart muscle weakness), a type of congenital heart disease. The proposal is also relevant to the PRMRP Topic Area of Mitochondrial Disease, since Barth syndrome is a mitochondrial disease. Both congenital heart disease and mitochondrial disease are “Areas of Encouragement” within the FY20 PRMRP Topic Areas. This study will most directly impact patients with Barth syndrome by increasing knowledge about disease mechanisms that may lead to new treatment strategies and by developing improved approaches to gene therapy. However, these studies will have wider impact. No approved gene therapies exist for heart disease or skeletal muscle disease, so this study may have impacts beyond this diagnosis by inspiring development of other gene therapy strategies. Our durable gene therapy strategy addresses a key concern for muscle gene therapy. Our study will also elucidate the links between altered cardiolipin and disease. Since cardiolipin is also altered in common conditions such as aging and diabetes, this knowledge may also have relevance to patients with those conditions.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110445
Entities
People
- William T. Pu
Organizations
- United States Army