Preselective gene therapy for fabry disease

Gangjian Qin, Toshihiro Takenaka, Kimberly Telsch, Leslie Kelley, Tazuko Howard, Thierry Levade, Robert Deans, Bruce H. Howard, Harry L. Malech, Roscoe O. Brady, Jeffrey A. Medin*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

66 Scopus citations


Fabry disease is a lipid storage disorder resulting from mutations in the gene encoding the enzyme (α-galactosidase A (α-gal A; EC We previously have demonstrated long-term (α-gal A enzyme correction and lipid reduction mediated by therapeutic ex vivo transduction and transplantation of hematopoietic cells in a mouse model of Fabry disease. We now report marked improvement in the efficiency of this gene-therapy approach. For this study we used a novel bicistronic retroviral vector that engineers expression of both the therapeutic α-gal A gene and the human IL-2Rα Chain (huCD25) gene as a selectable marker. Coexpression of huCD25 allowed selective immunoenrichment (preselection) of a variety of transduced human and murine cells, resulting in enhanced intracellular and secreted α-gal A enzyme activities. Of particular significance for clinical applicability, mobilized CD34+ peripheral blood hematopoietic stem/progenitor cells from Fabry patients have low-background huCD25 expression and could be enriched effectively after ex vivo transduction, resulting in increased α-gal A activity. We evaluated effects of preselection in the mouse model of Fabry disease. Preselection of transduced Fabry mouse bone marrow cells elevated the level of multilineage gene-corrected hematopoietic cells in the circulation of transplanted animals and improved in vivo enzymatic activity levels in plasma and organs for more than 6 months after both primary and secondary transplantation. These studies demonstrate the potential of using a huCD25-based preselection strategy to enhance the clinical utility of ex vivo hematopoietic stem/progenitor cell gene therapy of Fabry disease and other disorders.

Original languageEnglish (US)
Pages (from-to)3428-3433
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number6
StatePublished - Mar 13 2001

ASJC Scopus subject areas

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