Retroviral mutagenesis

Kung H.J., Baerkoel C., Carters T.H. (1991). Retroviral mutagenesis of cellular oncogenes a review with insights into the mechanisms of insertional activation. Curr. Top. Microbiol. Immunol. 171 1-25. 

Stocking, C. et al.. Distinct classes of factor-independent mutants can be isolated after retroviral mutagenesis of a human myeloid stem cell Hne, Growth Factors, 8,197,1993. 

The development of leukemia in patients receiving retrovirally transduced cells, clearly underlines that insertional mutagenesis is a major concern for integrating vectors. 

Retroviral insertional mutagenesis has been used for more than 2 decades to identify proto-oncogenes. More recently, a causal role of retroviral... 

Modlich U., Kustikova O.S., Schmidt M., Rudolph C., Meyer J., Li Z., Kamino K., von Neuhoff N., Schlegelberger B., Kuehlcke K., Bunting K.D., Schmidt S., Deichmann A., von Kalle C., Fehse B., Banm C. (2005) Lenkemias following retroviral transfer of multidrug resistance 1 (MDRl) are driven by combinatorial insertional mutagenesis. Blood Mi, 4235-4246. 

Suzuki, T., Minehata, K., Akagi, K., Jenkins, N.A. and Copeland, N.G. (2006) Tumor suppressor gene identification using retroviral insertional mutagenesis in Blm-defident mice. The EMBO Journal, 25, 3422-3431. 

Target Identification by Retroviral and Transposon-Driven Mutagenesis In GEMMs... 

Uren AG, Kool J, Berns A et al (2005) Retroviral insertional mutagenesis past, present and future. Oncogene 24 7656-7672... 

Williams KJ, Loeb LA. Retroviral reverse transcriptases Error frequencies and mutagenesis. Cun-Top Microbiol Immunol 1992 176 165-180. 

The lentiviral vectors have safety concerns similar to the retroviral vector-based gene therapy products (1) the production of a replication competent lentivirus (RCL) during manufacturing and (2) the potential for insertional mutagenesis, resulting in oncogene activation. One concern unique to the lentiviral vectors is the possibility that the vector can be mobilized in vivo,... 

The hazards of current vectors include insertion mutagenesis, immunogenesis, hepatotoxicity, and carcinogenic effects. In particular, retroviral vectors have a considerable carcinogenic potential. Adenoviruses, which do not integrate into the genome and consequently have only a transient effect, are considered to be safer. Also adeno-associated viruses have a low pathogenic potential in humans, as do lentiviruses. 

New, non-integrative reprogramming strategies that are safer in terms of risk of mutagenesis, and that are more efficient than the retroviral transfections, are very promising for both, potential clinical applications and drug screening applications. 

A potential safety factor to be monitored with retroviral vectors in human trials is the development of mutations following intracellular insertion of the vector material (i.e., insertional mutagenesis.) Another factor to be wary of is the appearance of replication-competent retroviruses from the same source (Muenchen et al., 1990). Other factors of concern would be vector-induced carcinogenesis by oncogene activation or other effects. One way to circumvent these potential difficulties is to utilize replication-incompetent vectors. 

---