Abstract
Barth syndrome (BTHS) is a rare mitochondrial disease that affects heart and skeletal muscle and has no curative treatment. It is caused by recessive mutations in the X-linked gene TAZ, which encodes tafazzin. To develop a clinically relevant gene therapy to restore tafazzin function and treat BTHS, three different adeno-associated virus serotype 9 vectors were tested and compared to identify the optimal promoter-cytomegalovirus (CMV), desmin (Des), or a native tafazzin promoter (Taz)-for TAZ expression following intravenous administration of 1 × 10 13 vector genomes/kilogram to a mouse model of BTHS as either neonates (1-2 days of age) or adults (3 months of age). At 5 months of age, evaluations of biodistribution and TAZ expression levels, mouse activity assessments, fatigue in response to exercise, muscle strength, cardiac function, mitochondrial structure, oxygen consumption, and electron transport chain complex activity assays were performed to measure the extent of improvement in treated mice. Each promoter was scored for significant improvement over untreated control mice and significant improvement compared with the other two promoters for every measurement and within each age of administration. All three of the promoters resulted in significant improvements in a majority of the assessments compared with untreated BTHS controls. When scored for overall effectiveness as a gene therapy, the Des promoter was found to provide improvement in the most assessments, followed by the CMV promoter, and finally Taz regardless of injection age. This study provides substantial support for translation of an adeno-associated virus serotype 9-mediated TAZ gene replacement strategy using a Des promoter for human BTHS patients in the clinic.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 139-154 |
| Number of pages | 16 |
| Journal | Human gene therapy |
| Volume | 30 |
| Issue number | 2 |
| DOIs | |
| State | Published - Feb 2019 |
Bibliographical note
Funding Information:The Barth Syndrome Foundation: Association Barth France and the Will McCurdy Fund for the Advancement of Therapies for Barth Syndrome (AGR DTD 03-06-2015; C.A.P.); Barth Syndrome Foundation of Canada (AGR DTD 7-14-2017; C.A.P.); the American Heart Association-Scientist Development (Grant No. 17SDG33410467; C.A.P.); the Children’s Miracle Network: University of Florida Pediatrics Pilot Project (C.A.P.); the National Institutes of Health (R01 HL136759-01A1; C.A.P.); and National Institutes of Health (R01 HL107406-01A1; W.T.C.) all provided funding support for this study. We would also like to acknowledge Dr. Xiao Xiao (University of North Carolina) for sharing the dsAAV vector, the University of Florida Vector Core facility for AAV production, and the Emory University Robert P. Apkarian Integrated Microscopy Core for EM processing and imaging.
Funding Information:
The Barth Syndrome Foundation: Association Barth France and the Will McCurdy Fund for the Advancement of Therapies for Barth Syndrome (AGR DTD 03-06-2015; C.A.P.); Barth Syndrome Foundation of Canada (AGR DTD 7-14-2017; C.A.P.); the American Heart Association-Scientist Development (Grant No. 17SDG33410467; C.A.P.); the Children's Miracle Network: University of Florida Pediatrics Pilot Project (C.A.P.); the National Institutes of Health (R01 HL136759-01A1; C.A.P.); and National Institutes of Health (R01 HL107406-01A1; W.T.C.) all provided funding support for this study. We would also like to acknowledge Dr. Xiao Xiao (University of North Carolina) for sharing the dsAAV vector, the University of Florida Vector Core facility for AAV production, and the Emory University Robert P. Apkarian Integrated Microscopy Core for EM processing and imaging.
Publisher Copyright:
© 2019, Mary Ann Liebert, Inc., publishers 2019.
Keywords
- cardiac gene therapy mitochondrial disease AAV9 tafazzin Barth syndrome promoter comparison