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Efficient correction of Fabry mice and patient cells mediated by lentiviral transduction of hematopoietic stem/progenitor cells

Gene Therapy volume 14, pages 256–265 (2007)Cite this article

Abstract

A deficiency in α-galactosidase A (α-gal A) activity causes Fabry disease. Virus-based delivery of genes can correct cells and establish a sustained supply of therapeutic proteins. Recombinant lentiviral vectors (LVs) show promise in this context. We first demonstrate LV-mediated marking of peripheral blood (PB) cells by transduction/transplantation of hematopoietic stem/progenitor cells. Stable enGFP expression was observed in PB for 37 weeks. Next, we transplanted Fabry mice with bone marrow mononuclear cells (BMMNCs) transduced a single time with a LV encoding the human α-gal A cDNA. Sustained expression of functional α-gal A in Fabry mice was observed over 24 weeks. Plasma α-gal A activity from treated Fabry mice was two-fold higher than wild-type controls. Increased α-gal A activity, often to supra-normal levels, and reduction of globotriaosylceramide, a glycolipid that accumulates in Fabry disease, was observed in all organs assessed. In secondary bone marrow transplantations, Fabry mice showed multilineage marking of PB, splenocytes and BMMNCs, along with therapeutic levels of α-gal A activity in plasma and organs over 20 weeks. Lastly, we transduced mobilized PB CD34+ cells from a Fabry patient and observed corresponding enzymatic increases. Thus a single LV-mediated transduction of primitive hematopoietic cells can result in sustained correction for Fabry disease.

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Acknowledgements

We thank Armando Poeppl and Gillian Sleep for technical assistance. This work was supported in part by NIH Grant HL70569 to JAM and a Roscoe Brady Genetic Diseases Fellowship to MY from the National Organization of Rare Diseases, Danbury, CT, USA.

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Authors and Affiliations

  1. Division of Stem Cell and Developmental Biology, Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada

    M Yoshimitsu, K Higuchi, T Nonaka, V I Rasaiah, C Siatskas, S-B Liang & J A Medin

  2. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada

    S Ramsubir & J A Medin

  3. Developmental and Metabolic Neurology Branch, NINDS,

    G J Murray & R O Brady

  4. NIH, Bethesda, MD, USA

    G J Murray & R O Brady

  5. The Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada

    J A Medin

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  1. M Yoshimitsu
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Yoshimitsu, M., Higuchi, K., Ramsubir, S. et al. Efficient correction of Fabry mice and patient cells mediated by lentiviral transduction of hematopoietic stem/progenitor cells. Gene Ther 14, 256–265 (2007). https://doi.org/10.1038/sj.gt.3302839

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