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Review
. 2013 Apr;50(2):101-30.
doi: 10.1053/j.seminhematol.2013.03.025.

Hematopoietic stem cell gene therapy:assessing the relevance of preclinical models

Andre Larochelle, Cynthia E Dunbar
Review

Hematopoietic stem cell gene therapy:assessing the relevance of preclinical models

Andre Larochelle et al. Semin Hematol. 2013 Apr.

Abstract

The modern laboratory mouse has become a central tool for biomedical research with a notable influence in the field of hematopoiesis. Application of retroviral-based gene transfer approaches to mouse hematopoietic stem cells (HSCs) has led to a sophisticated understanding of the hematopoietic hierarchy in this model. However, the assumption that gene transfer methodologies developed in the mouse could be similarly applied to human HSCs for the treatment of human diseases left the field of gene therapy in a decade-long quandary. It is not until more relevant humanized xenograft mouse models and phylogenetically related large animal species were used to optimize gene transfer methodologies that unequivocal clinical successes were achieved. However, the subsequent reporting of severe adverse events in these clinical trials casted doubts on the predictive value of conventional pre-clinical testing, and encouraged the development of new assays for assessing the relative genotoxicity of various vector designs.

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Figures

Figure 1
Figure 1. Approach for the genetic manipulation of hematopoietic stem cells (HSCs)
The upper panel compares the predictive value and accessibility of various preclinical models in the evaluation of gene transfer efficiency and insertional genotoxicity of vectors used in HSC gene therapy trials. The lower panel depicts the optimized protocol for transduction of hematopoietic stem and progenitor cells, as used in recent clinical trials. BM (bone marrow); Flt3L (fms-related tyrosine kinase 3 ligand); FN (fibronectin); IL3 (interleukin 3); MGDF (megakaryocyte growth and development factor); MLV (murine leukemia virus); MPBC (mobilized peripheral blood cells); SCF (stem cell factor); SIN (self-inactivating); TPO (thrombopoietin)
Figure 2
Figure 2. Timeline for the development of human gene therapy protocols targeting hematopoietic stem cells (HSCs)
The main phases in the evolution of HSC gene therapy clinical trials are ordered chronologically. The six principal features defining each phase are outlined. ADA (adenosine deaminase); ALD (adrenoleukodystrophy); BM (bone marrow); CB (cord blood); CGD (chronic granulomatous disease); Flt3L (fms-related tyrosine kinase 3 ligand); FN (fibronectin); HIV (human immunodeficiency virus); IL3 (interleukin 3); IL6 (interleukin 6); LSK (Lin−, Sca1+, Kit+); MGDF (megakaryocyte growth and development factor); MPBC (mobilized peripheral blood cells); SCF (stem cell factor); SCID (severe combined immunodeficiency disease); TPO (thrombopoietin); WAS (Wiskott-Aldrich syndrome)
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