Mutagenesis and oncogenesis by chromosomal insertion of gene transfer vectors.
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Mutagenesis and oncogenesis by chromosomal insertion of gene transfer vectors. / Baum, Christopher; Kustikova, Olga; Modlich, Ute; Li, Zhixiong; Fehse, Boris.
In: HUM GENE THER, Vol. 17, No. 3, 3, 2006, p. 253-263.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Mutagenesis and oncogenesis by chromosomal insertion of gene transfer vectors.
AU - Baum, Christopher
AU - Kustikova, Olga
AU - Modlich, Ute
AU - Li, Zhixiong
AU - Fehse, Boris
PY - 2006
Y1 - 2006
N2 - Increasing evidence reveals that random insertion of gene transfer vectors into the genome of repopulating hematopoietic cells may alter their fate in vivo. Although most insertional mutations are expected to have few if any consequences for cellular survival, clonal dominance caused by retroviral vector insertions in (or in the vicinity of) proto-oncogenes or other signaling genes has been described for both normal and malignant hematopoiesis. Important insights into these side effects were initially obtained in murine models. Results from ongoing clinical studies have revealed that similar adverse events may also occur in human gene therapy. However, it remains unknown to what extent the outcome of insertional mutagenesis induced by gene vectors is related to (1) the architecture and type of vector used, (2) intrinsic properties of the target cell, and (3) extrinsic and potentially disease-specific factors influencing clonal competition in vivo. This review discusses reports addressing these questions, underlining the need for models that demonstrate and quantify the functional consequences of insertional mutagenesis. Improving vector design appears to be the most straightforward approach to increase safety, provided all relevant cofactors are considered.
AB - Increasing evidence reveals that random insertion of gene transfer vectors into the genome of repopulating hematopoietic cells may alter their fate in vivo. Although most insertional mutations are expected to have few if any consequences for cellular survival, clonal dominance caused by retroviral vector insertions in (or in the vicinity of) proto-oncogenes or other signaling genes has been described for both normal and malignant hematopoiesis. Important insights into these side effects were initially obtained in murine models. Results from ongoing clinical studies have revealed that similar adverse events may also occur in human gene therapy. However, it remains unknown to what extent the outcome of insertional mutagenesis induced by gene vectors is related to (1) the architecture and type of vector used, (2) intrinsic properties of the target cell, and (3) extrinsic and potentially disease-specific factors influencing clonal competition in vivo. This review discusses reports addressing these questions, underlining the need for models that demonstrate and quantify the functional consequences of insertional mutagenesis. Improving vector design appears to be the most straightforward approach to increase safety, provided all relevant cofactors are considered.
M3 - SCORING: Zeitschriftenaufsatz
VL - 17
SP - 253
EP - 263
JO - HUM GENE THER
JF - HUM GENE THER
SN - 1043-0342
IS - 3
M1 - 3
ER -