Key result
AAV9-TAZ gene replacement in a mouse model of Barth syndrome significantly improved the expression levels of 91 proteins that were differentially expressed compared to wild-type controls.
Why the study?
Barth syndrome causes severe cardiomyopathy with no disease-modifying therapy, prompting evaluation of novel mechanistic pathways and the effects of gene therapy on cardiac proteomic profiles.
Does AAV9-TAZ gene replacement improve cardiac proteomic profiles in a mouse model of Barth syndrome?
Does AAV9-TAZ gene replacement improve cardiac proteomic profiles in a mouse model of Barth syndrome?
AAV9-TAZ gene replacement improves altered cardiac proteomic profiles in a mouse model of Barth syndrome, supporting its potential for clinical translation.
Supports AAV9-TAZ advancement to human trials in Barth syndrome; leaves open confirmation of clinical cardiac benefit.
Barth syndrome (BTHS) is a rare mitochondrial disease that causes severe cardiomyopathy and has no disease-modifying therapy. It is caused by recessive mutations in the gene tafazzin ( TAZ ), which encodes tafazzin—an acyltransferase that remodels the inner mitochondrial membrane lipid cardiolipin. To identify novel mechanistic pathways involved in BTHS and evaluate the effects of gene therapy on proteomic profiles, we performed a multiplex tandem mass tagging (TMT) quantitative proteomics analysis to compare protein expression profiles from heart lysates isolated from BTHS, healthy wild-type (WT), and BTHS treated with adeno-associated virus serotype 9 (AAV9)- TAZ gene replacement as neonates or adults. 197 proteins with ≥2 unique peptides were identified. Of these, 91 proteins were significantly differentially expressed in BTHS compared to WT controls. Cause-effect relationships between tafazzin deficiency and altered protein profiles were confirmed through demonstrated significant improvements in expression levels following administration of AAV9- TAZ . The importance of TMEM65 in Cx43 localization to cardiac intercalated discs was revealed as a novel consequence of tafazzin deficiency that was improved following gene therapy. This study identifies novel mechanistic pathways involved in the pathophysiology of BTHS, demonstrates the ability of gene delivery to improve protein expression profiles, and provides support for clinical translation of AAV9- TAZ gene therapy.
No takes yet. Share an insight, caveat, or question.
Suzuki‐Hatano et al. (2019) studied Barth syndrome (BTHS). AAV9-TAZ gene replacement vs. Untreated BTHS and healthy wild-type (WT) was evaluated on Protein expression profiles. AAV9-TAZ gene replacement in a mouse model of Barth syndrome significantly improved the expression levels of 91 proteins that were differentially expressed compared to wild-type controls.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: