The genetic engineering of hematopoietic stem cells: The rise of lentiviral vectors, the conundrum of the LTR, and the promise of lineage-restricted vectors Journal Article


Authors: Chang, A. H.; Sadelain, M.
Article Title: The genetic engineering of hematopoietic stem cells: The rise of lentiviral vectors, the conundrum of the LTR, and the promise of lineage-restricted vectors
Abstract: Recent studies on the integration patterns of different categories of retroviral vectors, the genotoxicity of long-terminal repeats (LTRs) and other genetic elements, the rise of lentiviral technology and the emergence of regulated vector systems providing tissue-restricted transgene expression and RNA interference, are profoundly changing the landscape of stem cell-based therapies. New developments in vector design and an increasing understanding of the mechanisms underlying insertional oncogenesis are ushering in a new phase in hematopoietic stem cell (HSC) engineering, thus bringing the hitherto exclusive reliance on LTR-driven, γ-retroviral vectors to an end. Based on their ability to transduce non-dividing cells and their genomic stability, lentiviral vectors offer new prospects for the manipulation of HSCs. Tissue-specific vectors, as exemplified by globin vectors, not only provide therapeutic efficacy, but may also enhance safety, insofar that they restrict transgene expression in stem cells, progenitor cells and blood cells in all but the transcriptionally targeted lineage. This review provides a survey of these advances as well as several remaining challenges, focusing in particular on the importance of achieving adequate levels of protein expression from a limited number of vector copies per cell - ideally one to two.
Keywords: protein expression; review; nonhuman; animals; gene targeting; proteasome inhibitor; gene expression; rna interference; genetic transcription; carmustine; carcinogenesis; cell lineage; gene transfer; gene vector; genetic transduction; genetic vectors; engraftment; genetic engineering; genomic instability; lentivirus; lentivirus vector; retrovirus vector; beta thalassemia; transgene; hematopoietic stem cells; safety; hematopoietic stem cell; combined immunodeficiency; blood clotting factor 9; genotoxicity; enzyme deficiency; hemophilia a; hemophilia b; long terminal repeat; tissue specificity; beta globin; sickle cell anemia; wiskott aldrich syndrome protein; wiskott aldrich syndrome; phosphoglycerate kinase; cell based gene therapy; hiv long terminal repeat
Journal Title: Molecular Therapy
Volume: 15
Issue: 3
ISSN: 1525-0016
Publisher: Nature Publishing Group  
Date Published: 2007-03-01
Start Page: 445
End Page: 456
Language: English
DOI: 10.1038/sj.mt.6300060
PUBMED: 17228317
PROVIDER: scopus
DOI/URL:
Notes: --- - "Cited By (since 1996): 40" - "Export Date: 17 November 2011" - "CODEN: MTOHC" - "Source: Scopus"
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  1. Alex Hongsheng Chang
    9 Chang
  2. Michel W J Sadelain
    519 Sadelain