AAV Gene Therapy Prevents and Reverses Heart Failure in a Murine Knockout Model of Barth Syndrome.

Circulation Research
Suya WangWilliam T Pu

Abstract

Barth syndrome is an X-linked cardiac and skeletal myopathy caused by mutation of the gene Tafazzin (TAZ). Currently, there is no targeted treatment for Barth syndrome. Lack of a proper genetic animal model that recapitulates the features of Barth syndrome has hindered understanding of disease pathogenesis and therapeutic development. We characterized murine germline TAZ knockout mice (TAZ-KO) and cardiomyocyte-specific TAZ knockout mice models and tested the efficacy of adeno-associated virus (AAV)-mediated gene replacement therapy with human TAZ (hTAZ). TAZ-KO caused embryonic and neonatal lethality, impaired growth, dilated cardiomyopathy, and skeletal myopathy. TAZ-KO mice that survived the neonatal period developed progressive, severe cardiac dysfunction, and fibrosis. Cardiomyocyte-specific inactivation of floxed Taz in cardiomyocytes using Myh6-Cre 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-hTAZ rescued neonatal death, cardiac dysfunction, and fibrosis in TAZ-KO mice, and both prevented and reversed established cardiac dysfunction in TAZ-KO and...Continue Reading

References

Apr 1, 1996·Nature Genetics·S BioneD Toniolo
Dec 19, 2000·Biochemical and Biophysical Research Communications·P VrekenP G Barth
Oct 17, 2003·The Journal of Biological Chemistry·Kathy PfeifferHermann Schägger
Dec 4, 2003·Molecular Microbiology·Zhiming GuMiriam L Greenberg
Dec 10, 2003·Journal of the American College of Cardiology·Michael SchlameThomas J J Blanck
Jan 13, 2006·Nature Chemical Biology·Valerian E KaganGregory G Borisenko
Jul 21, 2006·Proceedings of the National Academy of Sciences of the United States of America·Yang XuMichael Schlame
Jan 20, 2007·Molecular Therapy : the Journal of the American Society of Gene Therapy·Maja Z SalvaStephen D Hauschka
Dec 12, 2007·Clinical Chemistry·Willem KulikFrédéric M Vaz
Aug 7, 2008·Molecular Therapy : the Journal of the American Society of Gene Therapy·Douglas M McCarty
Aug 30, 2011·American Journal of Physiology. Heart and Circulatory Physiology·Carolyn T SpencerW Todd Cade
Sep 13, 2012·Molecular Therapy : the Journal of the American Society of Gene Therapy·Adeline VulinLuis Garcia
Oct 10, 2012·American Journal of Medical Genetics. Part a·Amy E RobertsCarolyn T Spencer
Feb 13, 2013·Orphanet Journal of Rare Diseases·Sarah L N ClarkeColin G Steward
Jun 12, 2013·Molecular Therapy : the Journal of the American Society of Gene Therapy·Maëva Le HirStéphanie Lorain
Oct 23, 2013·Chemistry and Physics of Lipids·Edgard M MejiaGrant M Hatch
Jun 27, 2015·PloS One·Laurence C CadalbertDouglas Strathdee
Jun 28, 2016·Nature Chemical Biology·Yang XuMichael Schlame
Aug 3, 2018·Human Gene Therapy·Silveli Suzuki-HatanoChristina A Pacak
Feb 13, 2019·Orphanet Journal of Rare Diseases·Brittany HornbyHilary J Vernon
Mar 28, 2019·The Journal of Cell Biology·Mindong RenMichael Schlame

❮ Previous
Next ❯

Citations

May 28, 2020·Journal of Developmental Biology·Michael T Chin, Simon J Conway
Sep 9, 2020·Journal of Cellular and Molecular Medicine·Lei LiuYifei Li
Oct 25, 2020·Cardiovascular Toxicology·Peng YueYifei Li
Feb 9, 2021·Frontiers in Cell and Developmental Biology·Hongyu LiaoYifei Li
Mar 1, 2021·Trends in Endocrinology and Metabolism : TEM·Micol FalabellaRobert D S Pitceathly
Mar 16, 2021·Frontiers in Pediatrics·Emanuele MondaGiuseppe Limongelli
Mar 8, 2021·Clinical and Experimental Pediatrics·Heeyoung SeokDa-Zhi Wang
Jul 25, 2021·International Journal of Molecular Sciences·Elena IgnatievaRenata Dmitrieva
Aug 10, 2021·Journal of Inherited Metabolic Disease·William T Pu
Aug 24, 2021·Journal of Inherited Metabolic Disease·Jan Dudek, Christoph Maack
Oct 30, 2021·Journal of Inherited Metabolic Disease·Reid ThompsonHilary J Vernon

❮ Previous
Next ❯

Datasets Mentioned

BETA
GM115593

Methods Mentioned

BETA
PCR
genotyping
electron microscopy
GTPase
gene replacement therapy

Software Mentioned

GraphPad Prism

Related Concepts

Related Feeds

Cardiomyopathy

Cardiomyopathy is a disease of the heart muscle, that can lead to muscular or electrical dysfunction of the heart. It is often an irreversible disease that is associated with a poor prognosis. There are different causes and classifications of cardiomyopathies. Here are the latest discoveries pertaining to this disease.