Insertion vectors for gene therapy

It goes without saying that efficient gene transfer is essential to gene therapy. Many different gene-transfer systems are being developed for numerous applications. Each of the envisaged applications has its own particular requirements and therefore a generally applicable, `ideal vector' does not exist. Vector systems are usually divided into those where the vector inserts itself into the host genome and those with vectors that remain extra-chromosomal. Integrated vectors are the system of choice if persistent expression is required. However, their insertion results in an alteration of the chromosomal DNA and therefore may lead to insertional mutagenesis. Although the risk of insertional mutagenesis is a recognized disadvantage, many gene therapy protocols embrace the use of integrating vectors. Apparently, the small possibility of adverse effects of insertion mutagenesis is not seen as a major obstacle for the use of integrating vectors for clinical gene therapy. Retroviruses are the archetype for vectors that integrate themselves into the host-cell genome. The murine retroviruses from which they are derived are notorious for their propensity to induce tumors in their natural hosts (hence their classification in the subfamily Oncovirinae). Once integrated, the provirus can perturb the expression of nearby cellular genes. In some instances, such a mutation can constitute a discrete step in the multistep process that eventually leads to cellular transformation. The unequalled efficiency with which retroviral vectors integrate their genome into the host-cell chromosomal DNA has made them the system of choice for many gene therapy applications. They have been used extensively in human gene therapy research. In more than 175 clinical trials, over 1600 patients have received retrovirus vectors. So far, not a single case has been reported in which adverse events have been attributed to insertional mutagenesis.