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Genotoxic potential of lineage-specific lentivirus vectors carrying the beta-globin locus control region.


ABSTRACT: Insertional mutagenesis by long terminal repeat (LTR) enhancers in gamma-retrovirus-based vectors (GVs) in clinical trials has prompted deeper investigations into vector genotoxicity. Experimentally, self-inactivating (SIN) lentivirus vectors (LVs) and GV containing internal promoters/enhancers show reduced genotoxicity, although strong ubiquitously-active enhancers dysregulate genes independent of vector type/design. Herein, we explored the genotoxicity of beta-globin (BG) locus control region (LCR), a strong long-range lineage-specific-enhancer, with/without insulator (Ins) elements in LV using primary hematopoietic progenitors to generate in vitro immortalization (IVIM) assay mutants. LCR-containing LV had approximately 200-fold lower transforming potential, compared to the conventional GV. The LCR perturbed expression of few genes in a 300 kilobase (kb) proviral vicinity but no upregulation of genes associated with cancer, including an erythroid-specific transcription factor occurred. A further twofold reduction in transforming activity was observed with insulated LCR-containing LV. Our data indicate that toxicology studies of LCR-containing LV in mice will likely not yield any insertional oncogenesis with the numbers of animals that can be practically studied.

SUBMITTER: Arumugam PI 

PROVIDER: S-EPMC2835044 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

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Genotoxic potential of lineage-specific lentivirus vectors carrying the beta-globin locus control region.

Arumugam Paritha I PI   Higashimoto Tomoyasu T   Urbinati Fabrizia F   Modlich Ute U   Nestheide Shawna S   Xia Ping P   Fox Catherine C   Corsinotti Andrea A   Baum Christopher C   Malik Punam P  

Molecular therapy : the journal of the American Society of Gene Therapy 20090825 11


Insertional mutagenesis by long terminal repeat (LTR) enhancers in gamma-retrovirus-based vectors (GVs) in clinical trials has prompted deeper investigations into vector genotoxicity. Experimentally, self-inactivating (SIN) lentivirus vectors (LVs) and GV containing internal promoters/enhancers show reduced genotoxicity, although strong ubiquitously-active enhancers dysregulate genes independent of vector type/design. Herein, we explored the genotoxicity of beta-globin (BG) locus control region  ...[more]

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