title: Aquaporin gene therapy corrects Sjögren's syndrome phenotype in mice.
abstract: Primary Sjögren's syndrome (pSS) is a chronic autoimmune disease that is estimated to affect 35 million people worldwide. Currently, no effective treatments exist for Sjögren's syndrome, and there is a limited understanding of the physiological mechanisms associated with xerostomia and hyposalivation. The present work revealed that aquaporin 5 expression, a water channel critical for salivary gland fluid secretion, is regulated by bone morphogenetic protein 6. Increased expression of this cytokine is strongly associated with the most common symptom of primary Sjögren's syndrome, the loss of salivary gland function. This finding led us to develop a therapy in the treatment of Sjögren's syndrome by increasing the water permeability of the gland to restore saliva flow. Our study demonstrates that the targeted increase of gland permeability not only resulted in the restoration of secretory gland function but also resolved the hallmark salivary gland inflammation and systemic inflammation associated with disease. Secretory function also increased in the lacrimal gland, suggesting this local therapy could treat the systemic symptoms associated with primary Sjögren's syndrome.
authors.affiliation: Adeno-Associated Virus Biology Section, Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892; Division of Biological Research on Drug Dependence, Department of Pharmaceutical Bioscience, Uppsala University, S-751 24 Uppsala, Sweden;
authors.forename: Zhennan
authors.initials: Z
authors.lastname: Lai
authors.affiliation: Adeno-Associated Virus Biology Section, Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Hongen
authors.initials: H
authors.lastname: Yin
authors.affiliation: Adeno-Associated Virus Biology Section, Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Javier
authors.initials: J
authors.lastname: Cabrera-Pérez
authors.affiliation: Adeno-Associated Virus Biology Section, Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Maria C
authors.initials: MC
authors.lastname: Guimaro
authors.affiliation: Adeno-Associated Virus Biology Section, Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Sandra
authors.initials: S
authors.lastname: Afione
authors.affiliation: Adeno-Associated Virus Biology Section, Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Drew G
authors.initials: DG
authors.lastname: Michael
authors.affiliation: Department of Pathology and Infectious Diseases, University of Florida, Gainesville, FL 32611.
authors.forename: Patricia
authors.initials: P
authors.lastname: Glenton
authors.affiliation: Adeno-Associated Virus Biology Section, Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Ankur
authors.initials: A
authors.lastname: Patel
authors.affiliation: Adeno-Associated Virus Biology Section, Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892;
authors.forename: William D
authors.initials: WD
authors.lastname: Swaim
authors.affiliation: Adeno-Associated Virus Biology Section, Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Changyu
authors.initials: C
authors.lastname: Zheng
authors.affiliation: Department of Pathology and Infectious Diseases, University of Florida, Gainesville, FL 32611.
authors.forename: Cuong Q
authors.initials: CQ
authors.lastname: Nguyen
authors.affiliation: Division of Biological Research on Drug Dependence, Department of Pharmaceutical Bioscience, Uppsala University, S-751 24 Uppsala, Sweden;
authors.forename: Fred
authors.initials: F
authors.lastname: Nyberg
authors.affiliation: Adeno-Associated Virus Biology Section, Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892; jchiorini@dir.nidcr.nih.gov.
authors.forename: John A
authors.initials: JA
authors.lastname: Chiorini
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D051398:Aquaporin 1 / Q000235:genetics*; D051402:Aquaporin 5 / Q000235:genetics* / Q000378:metabolism; D055418:Bone Morphogenetic Protein 6 / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002463:Cell Membrane Permeability; D015536:Down-Regulation; D005260:Female; D020868:Gene Silencing; D015316:Genetic Therapy; D006801:Humans; D007765:Lacrimal Apparatus / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008875:Middle Aged; D012469:Salivary Glands / Q000378:metabolism; D012859:Sjogren's Syndrome / Q000235:genetics / Q000628:therapy*; D014867:Water / Q000378:metabolism; D055815:Young Adult
chemical_list: C496020:AQP1 protein, human; C496036:AQP5 protein, human; D051402:Aquaporin 5; C525816:BMP6 protein, human; D055418:Bone Morphogenetic Protein 6; D014867:Water; D051398:Aquaporin 1
keywords: Sjögren’s syndrome; aquaporin; gene therapy