Phenotypic correction of lipid storage and growth arrest in Wolman disease fibroblasts by gene transfer of lysosomal acid lipase

U. J.F. Tietge, G. Sun, S. Czarnecki, Q. C. Yu, P. Lohse, H. Du, G. A. Grabowski, J. M. Glick, D. J. Rader

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

Wolman disease is a lethal lysosomal storage disease due to deficiency of lysosomal acid lipase (LAL). Wolman disease is characterized by pronounced hepatic involvement while neurological symptoms are uncommon, making Wolman disease an attractive candidate for liver-directed gene therapy. This study was performed to test the effects of gene replacement in fibroblasts lacking LAL, using a recombinant adenovirus encoding the human LAL cDNA (AdhLAL). Human fibroblasts from a Wolman disease patient were infected with AdhLAL and showed a dose-dependent increase in LAL protein and activity up to 5-fold above levels in control fibroblasts. Furthermore, 72 hr after infection with AdhLAL there was a dose-dependent correction of the severe lipid storage phenotype of Wolman disease fibroblasts. Electron microscopy confirmed significant correction of the lysosomal lipid storage in AdhLAL-infected Wolman disease fibroblasts at the ultrastructural level. Intravenous injection of AdhLAL into wild-type mice resulted in a 13.5-fold increase in hepatic LAL activity, and overexpression of LAL was not associated with toxic side effects. These data demonstrate high-level lysosomal expression of recombinant LAL in vitro and in vivo and show the feasibility of gene therapeutic strategies for the treatment of Wolman disease.

Original languageEnglish (US)
Pages (from-to)279-289
Number of pages11
JournalHuman gene therapy
Volume12
Issue number3
DOIs
StatePublished - Feb 10 2001

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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    Tietge, U. J. F., Sun, G., Czarnecki, S., Yu, Q. C., Lohse, P., Du, H., Grabowski, G. A., Glick, J. M., & Rader, D. J. (2001). Phenotypic correction of lipid storage and growth arrest in Wolman disease fibroblasts by gene transfer of lysosomal acid lipase. Human gene therapy, 12(3), 279-289. https://doi.org/10.1089/10430340150218413