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Blood, 1 March 2006, Vol. 107, No. 5, pp. 1751-1760.
Prepublished online as a Blood First Edition Paper on November 3, 2005; DOI 10.1182/blood-2005-06-2335.
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Submitted June 13, 2005
Accepted September 26, 2005
Survival of the fittest: In vivo selection and stem cell gene therapy
Tobias Neff, Brian C Beard, and Hans-Peter Kiem*
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; University of Washington School of Medicine, Seattle, WA, USA
* Corresponding author; email: hkiem{at}fhcrc.org.
Stem cell gene therapy has long been limited by low gene transfer efficiency to hematopoietic stem cells. Recent years have witnessed clinical success in select diseases such as X-linked SCID and ADA-deficiency. Arguably, the single most important factor responsible for the increased efficacy of these recent protocols is the fact that the genetic correction provided a selective in vivo survival advantage. Since, for most diseases, there will be no selective advantage of gene-corrected cells, there has been a significant effort to arm vectors with a survival advantage. Two-gene vectors can be used to introduce the therapeutic gene and selectable marker gene. Efficient in vivo selection strategies have been demonstrated in clinically relevant large animal models. Mutant forms of the DNA repair-enzyme methyl-guanine methyl-transferase in particular have allowed for efficient in vivo selection and have achieved sustained marking of virtually 100% gene-modified cells in large animals, with clinically acceptable toxicity. Translation of these strategies to the clinical setting is imminent. Here we review how in vivo selection strategies can be used to make stem cell gene therapy applicable to the treatment of a wider scope of genetic diseases and patients.
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