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AAV gene therapy prevents and reverses heart failure in a murine knockout model of Barth syndrome

RATIONALE: Barth syndrome (BTHS) is an X-linked recessive disorder caused by mutation of the gene Tafazzin (TAZ). Major clinical features include cardiac and skeletal myopathy. Currently there is no targeted treatment for BTHS. Lack of a proper genetic animal model that resembles the features of BTHS has hindered understanding of pathogenic mechanism and therapeutic development.

OBJECTIVEWe characterized novel murine germline (TAZ-KO) and cardiac specific (TAZ-CKO) Taz knockout models and tested the effectiveness of AAV-mediated TAZ gene replacement therapy in these models.

METHODS AND RESULTS: TAZ-KO caused embryonic and neonatal lethality, slow growth, dilated cardiomyopathy, and skeletal myopathy. TAZ-KO mice that survived the neonatal period developed progressive, severe cardiac contractile defects and fibrosis. Cardiomyocyte specific inactivation of floxed Taz in CMs using Cre recombinase driven by an Myh6 promoter caused progressive dilated cardiomyopathy without fetal or perinatal loss. Using both constitutive and conditional knockout models, we tested the efficacy and durability of Taz replacement by AAV gene therapy. Neonatal AAV-TAZ rescued neonatal death, cardiac dysfunction, and fibrosis in TAZ-KO mice, and both prevented and reversed established cardiac dysfunction in TAZ-KO and TAZ-CKO models. However, both neonatal and adult therapies required high CM transduction for durable efficacy.

CONCLUSIONS: TAZ-KO and TAZ-CKO mice mimic many of the key clinical features of BTHS. AAV-mediated gene replacement is efficacious when a sufficient fraction of CMs are transduced and treated.

Suya Wang1, Yifei Li1,2, Yang Xu3, Qing Ma1, Zhiqiang Lin1, Michael Schlame3,4, Vassilios Bezzerides1, Douglas Strathdee5, William Pu1,6

  1. Department of Cardiology, Boston Children’s Hospital, Boston, MA
  2. Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, China
  3. Department of Anesthesiology, New York University School of Medicine, New York, NY
  4. Department of Cell Biology, New York University School of Medicine, New York, NY
  5. Transgenic Technology Laboratory, Cancer Research UK Beatson Institute, Glasgow, UK
  6. Harvard Stem Cell Institute, Harvard University, Cambridge, MA

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