title: Evidence for the systemic delivery of a transgene product from salivary glands.
abstract: The aim of this study was to assess the feasibility of using gene transfer to salivary glands to direct the systemic delivery of therapeutic proteins in vivo. We used a replication-deficient recombinant adenovirus vector (Ad alpha 1AT) that encodes human alpha 1-antitrypsin (h alpha 1-AT), which we used as a marker protein. Ad alpha 1AT (5 x 10(9) pfu) was administered by retrograde ductal instillation to the submandibular glands of male rats. The amount of h alpha 1-AT found in the salivary glands, saliva, serum, and other tissues was analyzed by a sensitive enzyme-linked immunosorbent assay (ELISA). Maximal levels of the marker protein were detected at 24-48 hr post-virus administration for glands (274 ng/mg protein), saliva (approximately 313 ng/ml), and serum (approximately 5 ng/ml). Serum levels remained elevated for 96 hr, whereas the measured half-life for the marker protein was approximately 2 hr. Generally little to no h alpha 1-AT was detectable in most other organs. However, we were able to measure low levels of marker protein in tissues immediately surrounding infected glands. In all animals studied, levels of h alpha 1-AT were higher in the glandular venous effluent than in arterial blood. Similar results were found with parotid glands. The aggregate data demonstrate that salivary glands may be a target for the nonsurgical, systemic delivery of transgene-encoded therapeutic proteins for diseases that require relatively low circulating protein levels.
authors.affiliation: Clinical Investigations and Patient Care Branch, National Institute of Dental Research, National Institutes of Health, Bethesda, MD 20892-1190, USA.
authors.forename: H
authors.initials: H
authors.lastname: Kagami
authors.forename: B C
authors.initials: BC
authors.lastname: O'Connell
authors.forename: B J
authors.initials: BJ
authors.lastname: Baum
mesh_terms: D000260:Adenoviruses, Human / Q000235:genetics; D000818:Animals; D001774:Blood Chemical Analysis; D016503:Drug Delivery Systems; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D007765:Lacrimal Apparatus / Q000737:chemistry; D008198:Lymph Nodes / Q000737:chemistry; D008297:Male; D009132:Muscles / Q000737:chemistry; D010306:Parotid Gland / Q000737:chemistry; D011506:Proteins / Q000276:immunology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D012463:Saliva / Q000737:chemistry; D012469:Salivary Glands / Q000378:metabolism*; D000515:alpha 1-Antitrypsin / Q000235:genetics* / Q000276:immunology / Q000627:therapeutic use*
chemical_list: D011506:Proteins; D000515:alpha 1-Antitrypsin