alpha-Galactosidase A-Tat Fusion Enhances Storage Reduction in Hearts and Kidneys of Fabry Mice

作者：Higuchi Koji; Yoshimitsu Makoto; Fan Xin; Guo Xiaoxin; Rasaiah Vanessa I; Yen Jennifer; Tei Chuwa; Takenaka Toshihiro; Medin Jeffrey A^*

来源：Molecular Medicine, 2010, 16(5-6): 216-221.

DOI：10.2119/molmed.2009.00163

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.

• 出版日期2010-6
• 单位河北医科大学