Evidence for the systemic delivery of a transgene product from salivary glands.
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.
Kagami
H
H
Clinical Investigations and Patient Care Branch, National Institute of Dental Research, National Institutes of Health, Bethesda, MD 20892-1190, USA.
O'Connell
B C
BC
Baum
B J
BJ
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*
D011506:Proteins; D000515:alpha 1-Antitrypsin