The US and EU regulatory perspectives on the clinical use of hematopoietic stem/progenitor cells genetically modified ex vivo by retroviral vectors.

A primary safety issue presented by human hematopoietic stem cells/progenitor cells (HS/PC) genetically modified by gammaretroviral or lentiviral vectors is the risk of oncogenesis. This risk is a potential consequence of either of the following events: (a) the possible unintended generation of replication-competent vector-derived viruses (replication-competent retrovirus, RCR; replication-competent lentivirus, RCL) leading to neoplasia due to RCR/RCL infection of target and nontarget cells in vivo, or (b) intended vector integration in the chromosomal DNA of the target somatic cells leading to neoplasia due to insertional mutagenesis. These risks should be addressed in nonclinical and clinical studies. In the US and the EU, a combination of regulations and guidance documents are available to investigators and sponsors of gene therapy clinical trials. Guidance documents provide a facile way to adapt regulatory recommendations, in line with the changing state of the art in medical science. In the field of retroviral vectors, a number of innovations are being tested in nonclinical or clinical investigations, and each of these will raise their own regulatory issues. Some recent examples of these types of innovations include development of novel vector structures to minimize risks associated with vector integration, such as lentiviral vectors currently used in clinical trials for HS/PC modification that have been designed with deletions of the strong retroviral enhancer associated with oncogenesis.