Faculty Collaboration Database

Preselective gene therapy for Fabry disease. Proc Natl Acad Sci U S A 2001 Mar 13;98(6):3428-33

Date

03/15/2001

Pubmed ID

11248095

Pubmed Central ID

PMC30670

DOI

10.1073/pnas.061020598

Scopus ID

2-s2.0-0035853120 (requires institutional sign-in at Scopus site)   71 Citations

Abstract

Fabry disease is a lipid storage disorder resulting from mutations in the gene encoding the enzyme alpha-galactosidase A (alpha-gal A; EC ). We previously have demonstrated long-term alpha-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 alpha-gal A gene and the human IL-2Ralpha 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 alpha-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 alpha-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.

Author List

Qin G, Takenaka T, Telsch K, Kelley L, Howard T, Levade T, Deans R, Howard BH, Malech HL, Brady RO, Medin JA

Author

Jeffrey A. Medin PhD Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

3T3 Cells
Animals
Bone Marrow Transplantation
Disease Models, Animal
Fabry Disease
Gene Expression
Genetic Therapy
Genetic Vectors
HeLa Cells
Humans
Mice
Mice, Inbred C57BL
Receptors, Interleukin-2
Retroviridae
alpha-Galactosidase