oa Editorial [Hot Topic: Bacterial Vectors for Gene & Cell Therapy (Guest Editors: Mark Tangney & Cormac G.M. Gahan)]

The concept of exploiting bacterial species as biological gene vectors has existed for some time, and the use of bacteria to deliver therapeutics offers many advantages over other gene delivery approaches. Bacteria fall within the ‘non-viral’ class of delivery systems, investigated primarily for safety reasons, yet the biological nature of bacterial vectors means that many of the inherently beneficial traits of viral vectors are retained. A safety property unique to bacterial vectors is their sensitivity to clinically available antibiotic treatments, presenting control over the vector post-administration, an invaluable property for gene therapy. In terms of GMP-grade vector manufacture, the growth and production of live bacterial cultures has long been a focus of biotech industries both in the production of recombinant proteins and the production of live or killed vaccines. Bacterial vectors for delivery of therapeutic agents would therefore be relatively cheap and straightforward to produce on an industrial scale. In this issue, authors have focused primarily on individual bacterial genera that are particularly suited to specific applications in disease therapy and the reviews highlight the benefits and potential pitfalls of using these agents in human hosts. Because of the widely varying properties of different bacteria, a range of therapeutic strategies exists for bacterial vectors. Invasive pathogens are well suited to intracellular plasmid transfer (‘true’ gene delivery) (see reviews by Moreno et al.; Buttaro and Fruehauf; Tangney and Gahan), but their disease causing potential presents safety fears in terms of usage as systemically administered agents. At the opposite end of the spectrum, apathogenic species lacking the ability to deliver genes internally for mammalian cell expression, may safely be administered (IV, or even orally) to achieve systemic tumour targeting and bacterial expression of agents (cell therapy) (see Morrissey et al. review), or for mucosal therapeutic delivery e.g. to target inflammatory conditions of the gut (Bahey-el-Din et al. review). Furthermore, approaches can overlap, as exemplified by systemic administration of invasive strains of clostridial spores for tumour targeting with cancer cell invasion and bacterial induced oncolysis (see Mengesha et al. review), or oral administration of Salmonella resulting in tumour targeting and gene delivery or for vaccination purposes (see reviews by Moreno et al.; Tangney and Gahan). It is significant that many of the nascent bacterial delivery platforms described in this issue have entered or are currently entering human clinical trials. Use of clostridial species for targeted tumour killing and attenuated S. typhimurium vectors for oral vaccination or tumour gene delivery, represent the most widely applied bacterial vectors at clinical trial level [1-5]. Herein, Buttaro and Fruehauf describe FDA-related aspects of progression of these technologies through the phases of preclinical and clinical testing. They further describe a range of E. coli based vectors that have already been used in human trials. Also Lothar Stiedler and colleagues [6] have used live recombinant L. lactis expressing IL-10 as an active therapeutic in patients with Crohn's disease. It is also encouraging that an attenuated recombinant L. monocytogenes strain has recently been used as an anti-cancer vaccine vector in phase I trials in humans [7] (reviewed in Tangney and Gahan). Certainly, with the development and testing of vectors against cancer and infectious disease [8] we are closer to an era in which recombinant live bacterial vectors will be acceptable for therapeutic or prophylactic use provided they are proved to be safe and efficacious. Despite the massive potential of live bacterial delivery systems, it is clear that in many cases further work is required to limit potential adverse effects and to optimise delivery. Adverse effects may arise through non-specific inflammation triggered by interactions between microbial associated molecular patterns (such as LPS) and cognate toll-like receptors. There may be potential to limit these adverse responses in many cases through mutation of the vector, careful strain selection, coadministration of specific inhibitors or antibiotics and precise calculations of dose. Indeed, bacterial vectors may potentially be administered by oral, intranasal or intravenous routes of inoculation with a diverse range of resultant effects and outcomes (see Bahey-el-din et al., this issue). The concept of an orally administrated delivery vector is particularly attractive. However, for use of recombinant bacteria in humans, particular care must be taken to prevent lateral gene transfer in the gut (Buttaro and Fruehauf) and to limit environmental spread of the vector (Bahey-el-din et al.). With this latter concern in mind, a number of researchers have investigated the concept of ‘biological containment’ whereby the vector is engineered to survive in the host but not in the external environment where specific nutrients are limiting [9]. Overall the development of live bacterial vectors with potential for delivery of therapeutic agents is an exciting area of research that is gaining acceptance by clinicians and regulatory authorities for its potential to deliver positive clinical outcomes. Whilst more needs to be done to improve the safety and efficacy of some systems, this is clearly a technological approach which will yield dividends in the coming years.