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Prepublished online as a Blood First Edition Paper on January 2, 2003; DOI 10.1182/blood-2002-07-2314.
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Blood, 15 March 2003, Vol. 101, No. 6, pp. 2099-2113
REVIEW IN TRANSLATIONAL HEMATOLOGY
Side effects of retroviral gene transfer into hematopoietic stem
cells
Christopher Baum,
Jochen Düllmann,
Zhixiong Li,
Boris Fehse,
Johann Meyer,
David A. Williams, and
Christof von
Kalle
From the Department of Hematology and Oncology,
Hannover Medical School, Hannover, Germany; the Division
of Experimental Hematology, Cincinnati Children's Research Foundation,
Cincinnati, OH; the Departments of Neuroanatomy and Bone Marrow
Transplantation, University Hospital Eppendorf, Hamburg,
Germany; and the Department of Cell and Virus Genetics,
Heinrich Pette Institute, Hamburg, Germany.
Recent conceptual and technical improvements have resulted in
clinically meaningful levels of gene transfer into repopulating hematopoietic stem cells. At the same time, evidence is accumulating that gene therapy may induce several kinds of unexpected side effects,
based on preclinical and clinical data. To assess the therapeutic
potential of genetic interventions in hematopoietic cells, it will be
important to derive a classification of side effects, to obtain
insights into their underlying mechanisms, and to use rigorous
statistical approaches in comparing data. We here review side effects
related to target cell manipulation; vector production; transgene
insertion and expression; selection procedures for transgenic cells;
and immune surveillance. We also address some inherent differences
between hematopoiesis in the most commonly used animal model, the
laboratory mouse, and in humans. It is our intention to emphasize the
need for a critical and hypothesis-driven analysis of "transgene
toxicology," in order to improve safety, efficiency, and
prognosis for the yet small but expanding group of patients that could
benefit from gene therapy.
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