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.

[1]  Michael S. German,et al.  The endocrine secretion of human insulin and growth hormone by exocrine glands of the gastrointestinal tract , 1997, Nature Biotechnology.

[2]  B. Baum,et al.  Immediate inflammatory responses to adenovirus-mediated gene transfer in rat salivary glands. , 1996, Human gene therapy.

[3]  M. Kaleko,et al.  High-level tissue-specific expression of functional human factor VIII in mice. , 1996, Human gene therapy.

[4]  O. Danos,et al.  Long-term secretion of therapeutic proteins from genetically modified skeletal muscles. , 1996, Human gene therapy.

[5]  G. Proctor,et al.  Influences of secretory activities in rat submandibular glands on tissue kallikrein circulating in the blood , 1995, Experimental physiology.

[6]  Hanns Lochmüller,et al.  The route of administration is a major determinant of the transduction efficiency of rat tissues by adenoviral recombinants. , 1995, Gene therapy.

[7]  N. Sarvetnick,et al.  Cellular and humoral immune responses to adenoviral vectors containing factor IX gene: tolerization of factor IX and vector antigens allows for long-term expression. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[8]  R. Crystal,et al.  Administration of an adenovirus containing the human CFTR cDNA to the respiratory tract of individuals with cystic fibrosis , 1994, Nature Genetics.

[9]  M. Welsh,et al.  Safety and efficacy of repetitive adenovirus–mediated transfer of CFTR cDNA to airway epithelia of primates and cotton rats , 1994, Nature Genetics.

[10]  J. Wilson,et al.  Adenovirus-mediated transfer of the CFTR gene to lung of nonhuman primates: toxicity study. , 1993, Human gene therapy.

[11]  L. Smith,et al.  Hepatic gene therapy: adenovirus enhancement of receptor-mediated gene delivery and expression in primary hepatocytes. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[12]  J. Penschow,et al.  Secretion of glandular kallikrein and renin from the basolateral pole of mouse submandibular duct cells: an immunocytochemical study. , 1993, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[13]  J. Garlick,et al.  9 – Keratinocytes as a Target for Gene Therapy , 1993 .

[14]  M. Blumenberg,et al.  Molecular biology of the skin : the keratinocyte , 1993 .

[15]  K. Kurachi,et al.  Expression of human factor IX in mice after injection of genetically modified myoblasts. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[16]  K. Kurachi,et al.  Expression of human factor IX in rat capillary endothelial cells: toward somatic gene therapy for hemophilia B. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[17]  M. Perricaudet,et al.  Adenovirus-mediated transfer of a recombinant alpha 1-antitrypsin gene to the lung epithelium in vivo. , 1991, Science.

[18]  G. Darlington,et al.  Expression of human factor IX in rabbit hepatocytes by retrovirus-mediated gene transfer: potential for gene therapy of hemophilia B. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[19]  M. Perricaudet,et al.  Expression of human α1‐antitrypsin using a recombinant adenovirus vector , 1990 .

[20]  M. Mccarthy,et al.  A modified double antibody sandwich enzyme-linked immunosorbent assay for measurement of alpha-1-antitrypsin in biologic fluids. , 1985, Journal of immunological methods.

[21]  A. Hand,et al.  Basic Biological Sciences Regulation of Tight Junctional Permeability in the Rat Parotid Gland by Autonomic Agonists , 1984, Journal of dental research.

[22]  A. Hand,et al.  Alteration of tight junctional permeability in the rat parotid gland after isoproterenol stimulation , 1984, The Journal of cell biology.

[23]  H. Kuzuya,et al.  Transport to the bloodstream of amylase following retrograde infusion of amylase into the parotid glands in the rat. , 1984, Archives of oral biology.

[24]  B. Baum,et al.  Characteristics of Submandibular Glands from Young and Aged Rats , 1981, Journal of dental research.

[25]  N. Jones,et al.  Isolation of adenovirus type 5 host range deletion mutants defective for transformation of rat embryo cells , 1979, Cell.

[26]  S. Ishizaka,et al.  B Cell Activating Properties of Parotid Protein , 1979, Microbiology and immunology.

[27]  A. Hand,et al.  Uptake and fate of luminally administered horseradish peroxidase in resting and isoproterenol-stimulated rat parotid acinar cells , 1978, The Journal of cell biology.

[28]  J. J. Welsh,et al.  XV Cervical Lymphatics: Pathologic Conditions , 1966, The Annals of otology, rhinology, and laryngology.