Alpha-galactosidase A-Tat fusion enhances storage reduction in hearts and kidneys of Fabry mice. Mol Med 2010;16(5-6):216-21
Date
05/11/2010Pubmed ID
20454522Pubmed Central ID
PMC2864812DOI
10.2119/molmed.2009.00163Scopus ID
2-s2.0-77951963462 (requires institutional sign-in at Scopus site) 14 CitationsAbstract
The protein transduction domain from human immunodeficiency virus (HIV) Tat allows proteins to penetrate the cell membrane. Enhanced cellular uptake of therapeutic proteins could benefit a number of disorders. This is especially true for lysosomal storage disorders (LSDs) where enzyme replacement therapy (ERT) and gene therapy have been developed. We developed a novel recombinant lentiviral vector (LV) that engineers expression of alpha-galactosidase A (alpha-gal A)-Tat fusion protein for correction of Fabry disease, the second-most prevalent LSD with manifestations in the brain, kidney and heart. In vitro experiments confirmed mannose-6-phosphate independent uptake of the fusion factor. Next, concentrated therapeutic LV was injected into neonatal Fabry mice. Analysis of tissues at 26 wks demonstrated similar alpha-gal A enzyme activities but enhanced globotriaosylceramide (Gb3) reduction in hearts and kidneys compared with the alpha-gal A LV control. This strategy might advance not only gene therapy for Fabry disease and other LSDs, but also ERT, especially for cardiac Fabry disease.
Author List
Higuchi K, Yoshimitsu M, Fan X, Guo X, Rasaiah VI, Yen J, Tei C, Takenaka T, Medin JAAuthor
Jeffrey A. Medin PhD Professor in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsDisease Models, Animal
Enzyme Replacement Therapy
Fabry Disease
Genes, tat
Genetic Therapy
HIV
HeLa Cells
Humans
Kidney
Lentivirus
Mice
Myocardium
Reverse Transcriptase Polymerase Chain Reaction
Transduction, Genetic
Trihexosylceramides
alpha-Galactosidase
