Direct in vivo adenovirus-mediated gene transfer to salivary glands

Abstract

Gene transfer to the salivary glands holds the potential for the therapy of salivary gland disorders and for delivery of therapeutic proteins to the mouth and upper gastrointestinal tract. Administration of the recombinant adenovirus vectors Ad.RSV beta gal [coding for the intracellular protein beta-galactosidase (beta-Gal)] and Ad alpha 1AT [coding for human alpha 1-antitrypsin (alpha 1-AT), a secreted protein] to salivary gland cell lines in vitro demonstrated exogenous gene expression. Retrograde ductal injection of the Ad.RSV beta gal vector to rat salivary glands in vivo resulted in beta-Gal expression in acinar and ductal cells. Exposure of submandibular glands in vivo to Ad alpha 1AT resulted in expression of alpha 1-AT mRNA transcripts, de novo synthesis of alpha 1-AT, and secretion in the saliva. To evaluate the feasibility of adenovirus-mediated gene transfer to human glands, human minor salivary glands were infected ex vivo with Ad.RSV beta gal, and implanted into severe combined immunodeficient mice. Evaluation of the human tissue demonstrated beta-Gal activity. These observations demonstrate that adenovirus vectors are capable of direct delivery of genes to the salivary glands, suggesting a variety of possible gene therapy applications.

Safety and efficacy of adenovirus-mediated transfer of the human aquaporin-1 cDNA to irradiated parotid glands of non-human primates

“…10,16 Those studies have suggested several potentially useful clinical applications of this maneuver. Preclinical studies examining adenoviral-mediated gene transfer to the salivary glands of non-human primates should provide valuable information for eventual, planned human studies, based on the results of several studies using recombinant adenoviruses encoding the cystic fibrosis transmembrane conductance regulator.…”

“…10,11 Figure 5A demonstrates positive immunostaining for AQP1, primarily in capillaries and venules in control gland tissue (AdCMVH3; animal E). In animals receiving AdhAQP1, positive staining was seen in some acinar and ductal elements in addition to the vascular immunoreactivity.…”

Systemic action of human growth hormone following adenovirus-mediated gene transfer to rat submandibular glands

“…10,13 Each rat received 5 × 10 9 p.f.u. of AdCMVhGH in 50 l aliquots either by intramuscular injection (quadriceps), intravenous infusion (tail vein or femoral vein; with similar results) or by submandibular duct cannulation.…”

“…Salivary glands provide an extremely convenient target tissue for in vivo gene transfer. 13 These glands are readily accessible through the oral cavity, via their excretory ducts, without the need for surgical manipulations. Virtually all parenchymal cells in the gland line the ductal system and are potential targets for in vivo gene transfer.…”

“…Virtually all parenchymal cells in the gland line the ductal system and are potential targets for in vivo gene transfer. 13,14 Furthermore, salivary gland cells are physiologically endowed with the ability to produce copious amounts of secretory proteins (albeit for exocrine secretion), and thus may prove to be particularly useful for metabolic engineering. 1 The present report provides a fundamental extension of our initial observations concerning the systemic delivery of transgene products from salivary glands.…”