α-Galactosidase A-Tat Fusion Enhances Storage Reduction in Hearts and Kidneys of Fabry Mice
| Autor: | Makoto Yoshimitsu, Xiaoxin Guo, Chuwa Tei, Toshihiro Takenaka, Jeffrey A. Medin, Jennifer Yen, Koji Higuchi, Xin Fan, Vanessa I. Rasaiah |
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| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Genetic enhancement
Globotriaosylceramide Pharmacology Kidney Viral vector chemistry.chemical_compound Mice Transduction Genetic Genetics Medicine Animals Humans Enzyme Replacement Therapy Molecular Biology Genetics (clinical) business.industry Reverse Transcriptase Polymerase Chain Reaction Myocardium Trihexosylceramides Lentivirus HIV Enzyme replacement therapy Genetic Therapy medicine.disease Fabry disease Molecular medicine Fusion protein Disease Models Animal medicine.anatomical_structure chemistry Genes tat alpha-Galactosidase Molecular Medicine Fabry Disease business Research Article HeLa Cells |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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