Retroviral Vector Biosafety: Lessons from Sheep

[摘要] The safety of retroviral-based systems and the possibletransmission of replication-competent virus to patients is amajor concern associated with using retroviral vectors for genetherapy. While much effort has been put into the design of saferetroviral production methods and effective in vitro monitoringassays, there is little data evaluating the risks resulting fromretroviral vector instability at post-transduction stagesespecially following in vivo gene delivery. Here, we brieflydescribe and discuss our observations in an in vivo experimentalmodel based on the inoculation of retroviral vector-transducedtumor cells in sheep. Our data indicates that the in vivogeneration of mosaic viruses is a dynamic process and that virusvariants, generated by retroviral vector-mediated recombination,may be stored and persist in infected individuals prior toselection at the level of replication. Recombination may not onlyrestore essential viral functions or provide selective advantagesin a changing environment but also reestablish or enhance thepathogenic potential of the particular virus undergoingrecombination. These observations in sheep break new ground inour understanding of how retroviral vectors may have an impact onthe course of a preestablished disease or reactivate dormant orendogenous viruses. The in vivo aspects of vector stability raiseimportant biosafety issues for the future development of saferetroviral vector-based gene therapy.

[学科分类] 基础医学