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Review
. 2012 Feb 2;119(5):1107-16.
doi: 10.1182/blood-2011-09-349993. Epub 2011 Nov 17.

Hematopoietic stem cell engineering at a crossroads

Isabelle Rivière  1 , Cynthia E Dunbar, Michel Sadelain
Affiliations
Review

Hematopoietic stem cell engineering at a crossroads

Isabelle Rivière et al. Blood. .

Abstract

The genetic engineering of hematopoietic stem cells is the basis for potentially treating a large array of hereditary and acquired diseases, and stands as the paradigm for stem cell engineering in general. Recent clinical reports support the formidable promise of this approach but also highlight the limitations of the technologies used to date, which have on occasion resulted in clonal expansion, myelodysplasia, or leukemogenesis. New research directions, predicated on improved vector designs, targeted gene delivery or the therapeutic use of pluripotent stem cells, herald the advent of safer and more effective hematopoietic stem cell therapies that may transform medical practice. In this review, we place these recent advances in perspective, emphasizing the solutions emerging from a wave of new technologies and highlighting the challenges that lie ahead.

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Figures

Figure 1
Figure 1
Retroviral vector designs under clinical evaluation. (A) LTR-driven γ-RV, exemplified by the MFG/SFG vector design used in X-SCID and WAS clinical trials. (B) SIN-γ-RV, exemplified by the SRS11 EFS vector design used in the X-SCID consortium trial. (C) Nonspecific SIN-LV, exemplified by the MND-ALD vector design used in the ALD trial. (D) Lineage-restricted SIN-LV, exemplified by the TNS9.3 vector for the treatment of β-thalassemia major. U3 E/P indicates retroviral enhancer/promoter from the LTR U3 region; PRE/WPRE (woodchuck hepatitis), posttranscriptional regulatory element; SIN, self-inactivating vector design (▿ represents U3 deletion); specificity: − indicates ubiquitous; and +, lineage-specific; LCR, locus control region; and HBB, human β-globin gene. Green represents retroviral enhancer/promoter elements; and red, mammalian enhancer/promoter elements.
Figure 2
Figure 2
Evolving paradigms in HSC engineering. (A) Current strategies are restricted by the use of nonclonable adult HSCs. (B) The advent of patient-specific pluripotent stem cells may open new strategies for genetic engineering and biosafety testing.
See this image and copyright information in PMC

References

    1. Dunbar CE. Gene transfer to hematopoietic stem cells: implications for gene therapy of human disease. Annu Rev Med. 1996;47:11–20. - PubMed
    1. Kohn DB. Gene therapy for genetic haematological disorders and immunodeficiencies. J Intern Med. 2001;249(4):379–390. - PubMed
    1. Hacein-Bey-Abina S, von Kalle C, Schmidt M, et al. A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency. N Engl J Med. 2003;348(3):255–256. - PubMed
    1. Nienhuis AW, Dunbar CE, Sorrentino BP. Genotoxicity of retroviral integration in hematopoietic cells. Mol Ther. 2006;13(6):1031–1049. - PubMed
    1. Kustikova O, Brugman M, Baum C. The genomic risk of somatic gene therapy. Semin Cancer Biol. 2010;20(4):269–278. - PubMed

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