Intestinal delivery of non-viral gene therapeutics: physiological barriers and preclinical models

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The future of nucleic acid-based therapeutics is dependent on achieving successful delivery. Recently, there has been an increasing interest in delivery via the gastrointestinal tract. Gene therapy via this route has many advantages, including non-invasive access and the versatility to treat local diseases, such as inflammatory bowel disease, as well as systemic diseases, such as haemophilia.

The use of the gastrointestinal tract (GIT) as a site for the local delivery of gene therapeutics or as a route of delivery to distant sites is an exciting prospect. Several characteristics of the GIT make it an attractive target for gene therapy applications. First, the gut is readily accessible either by oral, rectal or endoscopic methods, facilitating access to target tissues without the need for invasive surgery. The oral route is of particular interest due to high patient compliance and reduced healthcare cost.

The large surface area of the gut means that a large population of cells is available for uptake. Another advantage to gut gene delivery is the presence of stem cells in the crypts of Lieberkuhn. These may be of particular interest in certain gene therapy applications as their successful transfection could, in some circumstances, facilitate long-term expression of therapeutic genes. Finally, the gut epithelium is highly vascularised, being located only a few microns from an extensive capillary network. This could provide access for therapeutic proteins synthesized in the gut (post gene transfer) to the systemic circulation and could be a promising strategy in the treatment of diseases, such as haemophilia. The potential delivery of nucleic acid therapies themselves to distant disease sites (e.g. tumours) following transport across the intestinal epithelial barrier (by transcellular or paracellular routes) is also of interest.

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