Successful TAT-mediated enzyme replacement therapy in a mouse model of mitochondrial E3 deficiency

Matan Rapoport, Lina Salman, Ofra Sabag, Mulchand S. Patel, Haya Lorberboum-Galski*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

37 Scopus citations


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.

Original languageAmerican English
Pages (from-to)161-170
Number of pages10
JournalJournal of Molecular Medicine
Issue number2
StatePublished - Feb 2011

Bibliographical note

Funding Information:
Acknowledgments This work was partially supported by grants from the United Mitochondrial Disease Foundation and Israel Science Foundation.


  • E3 mice
  • Enzyme replacement therapy
  • Lipoamide dehydrogenase (LAD) deficiency
  • Mitochondrial disorders
  • TAT


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