title: Successful TAT-mediated enzyme replacement therapy in a mouse model of mitochondrial E3 deficiency.
abstract: Medicine today offers no cure for patients suffering from mitochondrial disorders, such as lipoamide dehydrogenase (LAD; also known as E3) deficiency, and treatment is limited to symptomatic care. LAD is one of the components of the α-ketoacid dehydrogenase complexes, which are mitochondrial multienzyme complexes crucial for the metabolism of carbohydrates and amino acids. Recently, we tested the therapeutic approach for treating mitochondrial disorders whereby the activity of multicomponent complexes in the mitochondria is restored by TAT-mediated enzyme replacement therapy (ERT). The LAD deficiency disease was used before as a proof-of-principle in vitro, in patients' cells, utilizing the TAT-LAD fusion protein. In this report, we present successful TAT-mediated ERT in an in vivo mouse model using E3-deficient mice. We demonstrate the delivery of TAT-LAD into E3-deficient mice tissues and that a single administration of TAT-LAD results in a significant increase in the enzymatic activity of the mitochondrial multienzyme complex pyruvate dehydrogenase complex within the liver, heart and, most importantly, the brain of TAT-LAD-treated E3-deficient mice. We believe that this TAT-mediated ERT approach could change the management of mitochondrial disorders and of other metabolic diseases in modern medicine.
authors.affiliation: Department of Biochemistry and Molecular Biology, Institute for Medical Research-Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem, 91120, Israel.
authors.forename: Matan
authors.initials: M
authors.lastname: Rapoport
authors.forename: Lina
authors.initials: L
authors.lastname: Salman
authors.forename: Ofra
authors.initials: O
authors.lastname: Sabag
authors.forename: Mulchand S
authors.initials: MS
authors.lastname: Patel
authors.forename: Haya
authors.initials: H
authors.lastname: Lorberboum-Galski
mesh_terms: D000818:Animals; D008058:Dihydrolipoamide Dehydrogenase / Q000172:deficiency* / Q000378:metabolism; D004195:Disease Models, Animal; D056947:Enzyme Replacement Therapy; D005786:Gene Expression Regulation; D015696:Gene Products, tat / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D009928:Organ Specificity / Q000235:genetics; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology
chemical_list: D015696:Gene Products, tat; D011768:Pyruvate Dehydrogenase Complex; D011993:Recombinant Fusion Proteins; D008058:Dihydrolipoamide Dehydrogenase