Aquaporin gene therapy corrects Sjögren's syndrome phenotype in mice

Proc Natl Acad Sci U S A. 2016 May 17;113(20):5694-9. doi: 10.1073/pnas.1601992113. Epub 2016 May 2.

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.

Keywords: Sjögren’s syndrome; aquaporin; gene therapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Animals
  • Aquaporin 1 / genetics*
  • Aquaporin 5 / genetics*
  • Aquaporin 5 / metabolism
  • Bone Morphogenetic Protein 6 / genetics
  • Bone Morphogenetic Protein 6 / metabolism
  • Cell Line
  • Cell Membrane Permeability
  • Down-Regulation
  • Female
  • Gene Silencing
  • Genetic Therapy*
  • Humans
  • Lacrimal Apparatus / metabolism
  • Male
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Middle Aged
  • Salivary Glands / metabolism
  • Sjogren's Syndrome / genetics
  • Sjogren's Syndrome / therapy*
  • Water / metabolism
  • Young Adult

Substances

  • AQP1 protein, human
  • AQP5 protein, human
  • Aquaporin 5
  • BMP6 protein, human
  • Bone Morphogenetic Protein 6
  • Water
  • Aquaporin 1