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Various Cells Retrovirally Transduced with N -Acetylgalactosoamine-6-Sulfate Sulfatase Correct Morquio Skin Fibroblasts In Vitro

Authors
  • Gabriele Toietta
  • Giovanni Severini
  • Catia Traversari
  • Shunji Tomatsu
  • Kazuko Sukegawa
  • Seiji Fukuda
  • Naomi Kondo
  • Paolo Tortora
  • Claudio Bordignon
Type
Published Article
Journal
Human Gene Therapy
Publisher
Mary Ann Liebert
Publication Date
Nov 08, 2001
Volume
12
Issue
16
Pages
2007–2016
Identifiers
DOI: 10.1089/104303401753204571
PMID: 11686941
Source
MyScienceWork
Keywords
License
Green

Abstract

Gene therapy may provide a long-term approach to the treatment of mucopolysaccharidoses. As a first step toward the development of an effective gene therapy for mucopolysaccharidosis type IVA (Morquio syndrome), a recombinant retroviral vector, LGSN, derived from the LXSN vector, containing a full-length human wild-type N-acetylgalactosamine-6-sulfate sulfatase (GALNS) cDNA, was produced. Severe Morquio and normal donor fibroblasts were transduced by LGSN. GALNS activity in both Morquio and normal transduced cells was several fold higher than normal values. To measure the variability of GALNS expression among different transduced cells, we transduced normal and Morquio lymphoblastoid B cells and PBLs, human ker-atinocytes, murine myoblasts C2C12, and rabbit synoviocytes HIG-82 with LGSN. In all cases, an increase of GALNS activity after transduction was measured. In Morquio cells co-cultivated with enzyme-deficient trans-duced cells, we demonstrated enzyme uptake and persistence of GALNS activity above normal levels for up to 6 days. The uptake was mannose-6-phosphate dependent. Furthermore, we achieved clear evidence that LGSN transduction of Morquio fibroblasts led to correction of the metabolic defect. These results provide the first evidence that GALNS may be delivered either locally or systematically by various cells in an ex vivo gene therapy of MPS IVA. 2007 OVERVIEW SUMMARY Gene therapy is actively being considered for the treatment of mucopolysaccharidoses and other lysosomal diseases. The importance of evaluating this approach is emphasized by the lack of any effective alternative. Here, we show retro-virus-mediated gene correction of MPS IVA (N-acetyl-galactosamine-6-sulfate sulfatase deficiency) fibroblasts and the transfer of GALNS from retrovirally transduced cells to Morquio cells.

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