Abstract 16604: Recombinant Tafazzin Enzyme Replacement Therapy Rescues Metabolic and Functional Defects in a Mouse Model of Barth Syndrome

Abstract

Barth syndrome (BTHS) is an X-linked autosomal recessive disease caused by mutations in the tafazzin (TAZ) gene. These mutations lead to hypotonia, cyclic neutropenia, 3-methyglutaconic aciduria, and the most common cause of mortality in patients, cardiomyopathy. The TAZ gene encodes an enzyme that generates mature cardiolipin (CL) from monolysocardiolipin (MLCL)in the mitochondrial membrane, which is essential for normal mitochondrial morphology and function. Currently, there is no effective therapy for BTHS. In this study, we test an enzyme replacement therapy for BTHS in myocardial-specific TAZ conditional knockout mice which model the cardiomyopathy of BTHS. Serial echocardiograms showed that the BTHS mice developed increased septal wall thickness at 5 weeks of age. The BTHS mice were treated for 12 weeks with either vehicle or recombinant human TAZ fused to a cell penetrating peptide (hTAZ-CTP) to facilitate tissue uptake. During the treatment period, septal wall thickness in the vehicle-treated mouse continued to increase, whereas it remained stable in those treated with hTAZ-CTP . Pressure-volume (PV) loop analysis indicated that heart function was impaired in the vehicle-treated BTHS mouse while the protein-treated mice were shown to have PV loops similar to normal mice. The ratio of MLCL/CL, a direct measure of TAZ enzymatic activity, was measured in heart mitochondria isolated from BTHS and control floxed allele mice after treatment. The MLCL/CL ratio in the vehicle treated BTHS mouse was 20.4, consistent with a BTHS phenotype, whereas the MLCL/CL ratios in protein-treated and control mice were 0.01, indicating that injection of hTAZ-CTP successfully rescued the function of TAZ in BTHS mice. Histological observation of liver, spleen, kidney, and heart did not show any sign of toxicity for hTAZ-CTP injection. These results indicate that TAZ enzyme replacement therapy has great potential as a future treatment for BTHS.