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Gene Transfer for Chemoprotection and Enrichment of Hematopoietic Stem Cells

  • Chapter
Gene Therapy for Cancer

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

Abstract

Hematopoietic stem cells (HSCs) have been the archetypal target for therapeutic gene transfer strategies, due to the ease with which these cells are obtained and cultured ex vivo, as well as their capacity for reconstituting an entire tissue type. The myelosuppressive consequence of neoplastic disease treatment has provided additional thrust for the development of HSC drug-resistance and gene transfer strategies. In this regard, significant advances in vector design have been achieved by careful evaluation of different promoter and enhancer sequences, as well as exogenous elements, that contribute to high gene expression levels and resist positional effect variegation. Gene transfer efficiencies have also been improved by the identification of envelope pseudotypes that recognize receptors expressed in the more primitive hematopoietic populations. In addition, several natural and synthetic gene products have been evaluated as tools for amplifying or enriching gene-modified HSCs in vivo. These include the homeobox transcription factors, selective amplifier genes, and drug resistance genes. The ability to enrich and repopulate the hematopoietic compartment with therapeutic gene-corrected cells requires strategies that act on primitive progenitor populations, and vectors that efficiently express multiple gene products. The realization of insertional mutagenesis has demonstrated the importance of therapy-related risk assessment and the need for vectors with inherent cell-type specificities. These advances have culminated in enhanced HSC gene transfer and enrichment, while highlighting areas requiring further development.

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Authors and Affiliations

  1. Division of Hematology/Oncology, Case Western Reserve University, Cleveland, OH

    Justin C. Roth PhD

  2. Division of Hematology-Oncology, Case Western Reserve University School of Medicine, Cleveland, OH

    Stanton L. Gerson MD

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  1. Justin C. Roth PhD
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  2. Stanton L. Gerson MD
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  1. The University of Texas M. D. Anderson Cancer Center, Houston, TX

    Kelly K. Hunt MD  & Stephen G. Swisher MD  & 

  2. Inselspital Bern, University of Bern, Bern, Switzerland

    Stephan A. Vorburger MD, MCR

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Roth, J.C., Gerson, S.L. (2007). Gene Transfer for Chemoprotection and Enrichment of Hematopoietic Stem Cells. In: Hunt, K.K., Vorburger, S.A., Swisher, S.G. (eds) Gene Therapy for Cancer. Cancer Drug Discovery and Development. Humana Press. https://doi.org/10.1007/978-1-59745-222-9_16

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