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Stem cell–derived erythroid cells mediate long-term systemic protein delivery

Nature Biotechnology volume 24, pages 1017–1021 (2006)Cite this article

Abstract

We demonstrate here the capacity of erythroid cells to mediate long-term, systemic and therapeutic protein delivery in vivo. By targeting human factor IX (hFIX) expression to late-stage erythropoiesis, we achieve long-term hFIX secretion at levels significantly higher (>tenfold) than those obtained with an archetypal ubiquitous promoter in a mouse model of hemophilia B. Erythroid cell–derived hFIX is biologically active, resulting in phenotypic correction of the bleeding disorder. In addition to achieving high expression levels and resistance to transcriptional silencing, red cell–mediated protein delivery offers multiple advantages including immune tolerance induction, reduction of the risk of insertional oncogenesis and relative ease of application by either engrafting transduced hematopoietic stem cells or transfusing ex vivo–generated, stem cell–derived erythroid cells.

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Figure 1: Structure and in vitro function of erythroid-specific lentiviral vectors.
Figure 2: Long-term secretion of hFIX in RT9-hFIX-SI–transduced bone marrow chimeras.
Figure 3: Erythroid-specific expression of hFIX in vivo.
Figure 4: Lack of humoral immune response against hFIX and strong tolerance induction.

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Acknowledgements

We thank Inder Verma for providing the C57BL/6-FIX−/− mice. This work was supported by National Institutes of Health grants HL66952, HL57612, CA59350 and CA08748; by the Leonardo Giambrone Foundation; and by Mr. William H. Goodwin, Mrs. Alice Goodwin and the Commonwealth Cancer Foundation for Research. A.H.C. is the recipient of a scholarship from the Program of Excellence in Gene Therapy (PEGT) program. M.T.S. is the recipient of a predoctoral fellowship from the Cancer Research Institute.

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Authors and Affiliations

  1. Laboratory of Gene Transfer and Gene Expression, Memorial Sloan-Kettering Cancer Center, New York, 10021, New York, USA

    Alex H Chang, Matthias T Stephan & Michel Sadelain

  2. Immunology Graduate Program, Weill Graduate School of Medical Sciences, Cornell University, New York, 10021, New York, USA

    Matthias T Stephan

  3. Gene Transfer and Somatic Cell Engineering Facility, Memorial Sloan-Kettering Cancer Center, New York, 10021, New York, USA

    Michel Sadelain

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Correspondence to Michel Sadelain.

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Chang, A., Stephan, M. & Sadelain, M. Stem cell–derived erythroid cells mediate long-term systemic protein delivery. Nat Biotechnol 24, 1017–1021 (2006). https://doi.org/10.1038/nbt1227

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