Recombinant adeno-associated virus serotype 2 vectors mediate stable interleukin 10 secretion from salivary glands into the bloodstream

Seiichi Yamano, Li Yun Huang, Chuantian Ding, John A. Chiorini, Corinne M. Goldsmith, Robert B. Wellner, Basil Golding, Robert M. Kotin, Dorothy E. Scott, Bruce J. Baum

Research output: Contribution to journalArticle

Abstract

We have constructed a recombinant adeno-associated virus serotype 2 vector encoding human interleukin 10 (rAAVhIL10). IL-10 is a potent antiinflammatory/immune cytokine, which has received growing attention for its therapeutic potential. Human IL-10 (hIL-10) production was virus dose dependent after in vitro infection of HSG cells, a human submandibular gland cell line. The vector-derived hIL-10 produced was biologically active, as the medium from rAAVhIL10-infected HSG cells caused a dose-dependent blockade of IL-12 secretion from spleen cells of IL-10 knockout mice challenged with heat-killed Brucella abortus. Administration of rAAVhIL10 (1010genomes per gland) to both mouse submandibular glands led to hIL-10 secretion into the bloodstream (∼1-5 pg/ml), that is, in an endocrine manner, which was stable for ∼ 2 months. Salivary gland administration of rAAVhIL10 under experimental conditions was more efficacious than intravenous administration (∼0.5-0.7 pg/ml). Also, hIL-10 was readily secreted in vitro from organ cultures of minced submandibular glands infected with rAAVhIL10, 6 or 8 weeks earlier. Consistent with these results, hIL-10 mRNA was detected by reverse transcription-polymerase chain reaction in submandibular glands of mice infected with rAAVhIL10 but not from control mice. At these doses, little to no hIL-10 was detected in mouse saliva. Using a rAAV serotype 2 vector encoding β-galactosidase, we observed that the primary parenchymal target cells were ductal. These findings represent the first report of rAAV use to target exocrine glands for systemic secretion of a therapeutic protein, and support the notion that rAAV serotype 2 vectors may be useful in salivary glands for local (periglandular) and systemic gene-based protein therapeutics.

Original languageEnglish (US)
Pages (from-to)287-298
Number of pages12
JournalHuman Gene Therapy
Volume13
Issue number2
DOIs
StatePublished - 2002

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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    Yamano, S., Huang, L. Y., Ding, C., Chiorini, J. A., Goldsmith, C. M., Wellner, R. B., Golding, B., Kotin, R. M., Scott, D. E., & Baum, B. J. (2002). Recombinant adeno-associated virus serotype 2 vectors mediate stable interleukin 10 secretion from salivary glands into the bloodstream. Human Gene Therapy, 13(2), 287-298. https://doi.org/10.1089/10430340252769806