Viral hybrid-vectors for delivery of autonomous replicons

Gene therapeutic approaches offer great opportunities to treat genetic diseases which require long-term effects after a single administration of a customized vector. For these specific approaches the optimal vector system should combine the following features: (1) it should efficiently transport the genetic cargo into target cells in vitro or in vivo, (2) it should lead to sufficient long-term expression of the therapeutic transgene, (3) it should not interfere with the expression profile or the composition of the host genome, and (4) it should not result in unwanted side effects such as immune responses or other toxic effects. Predominantly used vectors for maintenance of therapeutic DNA and long-term transgene expression in preclinical and clinical studies are based on integrase-, recombinase-, transposase- or designer nuclease-mediated somatic integration into the host genome. However, for these systems the risk of insertional mutagenesis represents a potential unwanted adverse event. Therefore, autonomously replicating genetic elements were developed and there is accumulating evidence that these episomal vectors which are maintained extrachromosomally are suitable for therapeutic applications in dividing cells. In this review we provide a state-of-the-art overview of used viral hybrid-vectors which efficiently deliver autonomous DNA (plasmid replicon pEPI and Epstein-Barr Virus-based replicons) and RNA replicons (Semliki Forest Virus replicons) into target cells. To date adenoviruses, herpesviruses and baculovirus were explored for efficient delivery of autonomous replicons into various cell types and tissues. Applications and advantages and limitations of these hybrid-vectors are discussed in this review. We believe that with further optimization autonomous replicons may play an increasingly important role in gene therapeutic applications.