The recent incidents of leukemia development in X-SCID patients after a 
successful treatment of the disease with retroviral gene therapy raised concerns 
regarding the safety of the use of retroviral vectors in clinical gene therapy. 
In this review, we have tried to re-evaluate the safety issues related to the 
use of retroviral vectors in human clinical trials and to suggest possible 
appropriate solutions to the issues. As revealed by the X-SCID incident, 
oncogenesis caused by retroviral insertional activation of host genes is one of 
the most prominent risks. An ultimate solution to this problem will be in 
re-engineering retroviral vectors so that the retroviral insertion takes place 
only at the desired specific sites of the host cell chromosome. This is, 
however, a technically demanding tasks, and it will take years to develop 
retroviral vectors with targeted insertion capability. In the mean time, the use 
of chromatin insulators can reduce chances for retrovirus-mediated oncogenesis 
by inhibiting non-specific activation of nearby cellular proto-oncogenes. 
Co-transduction of a suicidal gene under the control of an inducible promoter 
could also be one of the important safety features, since destruction of 
transduced cells can be triggered if abnormal growth is observed. Additionally, 
conditional expression of the transgene only in appropriate target cells via the 
combination of targeted transduction, cell type-specific expression, and 
targeted local administration will increase the overall safety of the retroviral 
systems. Finally, splitting of the viral genome, use of self-inactivating (SIN) 
retroviral vectors, or complete removal of the coding sequences for gag, pol, 
and env genes is desirable to virtually eliminate the possibility of generation 
of replication competent retroviruses (RCR).