Abstract P2171: Lentivirus TAZ Gene Therapy Restores Metabolic Functions In Taz Ko Mice Model Of Barth Syndrome

Abstract

Introduction: Barth Syndrome is an X-linked disorder caused by mutation in thegene encoding tafazzin (or TAZ ), characterized by dilated cardiomyopathy, muscularhypotonia and cyclic neutropenia. TAZ is a mitochondrial acyltransferase that generatesmature cardiolipin (CL) from monolysocardiolipin (MLCL) and is essential formitochondrial morphology and function. Patients with BTHS exhibit a characteristicreduction in the levels of CL and an accumulation of MLCL. Currently, there is no targetedtreatment exists for these patients. We characterized a global TAZ knockout mousemodel of BTHS and tested the efficacy of Lentivirus-mediated TAZ gene therapy. Methods: We generated third generation lentiviral constructs without an insert, withGreen Fluorescent Protein, with recombinant tafazzin and with recombinant tafazzinmodified to contain a cellular penetrating peptide (hTAZ-CPP) that promotes uptake intotafazzin-deficient cells. We tested the efficacy of these recombinant lentiviruses, first inmouse embryo fibroblasts (MEF) isolated from tafazzin knockout mice and then intafazzin knockout mice after systemic administration. Results: We have found that treatment with hTAZ-CPPs reduces the MLCL/CL ratio tonear wild type levels, thereby rescuing the defect in cardiolipin remodeling in TAZ KOMEFs. Serial echocardiograms revealed significant increase in septal wall thickness andsignificant decrease in ejection fraction, fractional shortening and global longitudinal strainin TAZ KO mice. The TAZ KO mice were treated systemic lentivirus at 5 weeks of ageand then echocardiograms were performed at every 4 weeks until 16 weeks. After thetreatment septal wall thickness continued to increase and ejection fraction, fractionalshortening and global longitudinal strain continued to decrease in the empty virus or GFPtreated mice, whereas they are remained stable in those treated with hTAZ-CPPs. Conclusion: These findings suggest that Lentivirus-mediated TAZ gene replacementtherapy enhanced with cell penetrating peptides has potential as a future treatment forBTHS.