Uncovering and dissecting the genotoxicity of self-inactivating lentiviral vectors in vivo.

ABSTRACT: Self-inactivating (SIN) lentiviral vectors (LV) have an excellent therapeutic potential as demonstrated in preclinical studies and clinical trials. However, weaker mechanisms of insertional mutagenesis could still pose a significant risk in clinical applications. Taking advantage of novel in vivo genotoxicity assays, we tested a battery of LV constructs, including some with clinically relevant designs, and found that oncogene activation by promoter insertion is the most powerful mechanism of early vector-induced oncogenesis. SIN LVs disabled in their capacity to activate oncogenes by promoter insertion were less genotoxic and induced tumors by enhancer-mediated activation of oncogenes with efficiency that was proportional to the strength of the promoter used. On the other hand, when enhanc

SUBMITTER: Cesana D 

PROVIDER: S-EPMC3982501 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature