Salivary secretions maintain the health of the oral cavity. Building on our past studies of saliva formation and its alteration during pathology, we are developing novel approaches to treat salivary gland dysfunction using principles of gene therapy and tissue engineering. During this reporting period we have addressed fundamental and practical questions necessary to move such approaches into the clinic. For example, we are working to design an optimal transgene cassette, using a variety of different promoters and other elements, to enhance expression after salivary gland gene transfer. To determine which viral vector facilitates optimal salivary expression we are testing several adenoassociated virus (AAV) serotypes (2, 4, 5), conventional E1/E3 deficient adenoviral vectors, and hybrid (adenoviral with retroviral elements) vectors in rodent models using erythropoeitin as a therapeutically relevant reporter gene. We also have extended past studies on the hybrid adeno-retroviral vector, and clearly shown that it infects and transduces epithelial cells like a conventional adenoviral vector, but integrates into genomic DNA much more frequently. Additionally, we began to employ the AAV serotype 2 vector encoding human IL-10 reported last year, administering it to NOD mouse submandibular glands. This maneuver prevented age and gender-related autoimmune associated salivary flow reductions and diminished glandular lymphocytic infiltrates in this model of Sjogren?s syndrome. We also completed a detailed study of the toxicology and biodistribution of an adenoviral vector administered to a single rat submandibular gland. In general, there were no adverse systemic consequences to animals over the course of this study (15 days). We have also made progress in finding a possible autologous cell source for the artificial salivary gland device from an unexpected source, hematopoetic progenitor cells (see DE00704).
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