July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
Rapid-aging Xpg-/- mice model age-related retinal inflammation
Author Affiliations & Notes
  • Faye M Drawnel
    Pharma Research and Early Development, F. Hoffmann-LaRoche Ltd., Basel, Switzerland
  • Olivia O'Leary
    Pharma Research and Early Development, F. Hoffmann-LaRoche Ltd., Basel, Switzerland
  • Tabea Grossenbacher
    Pharma Research and Early Development, F. Hoffmann-LaRoche Ltd., Basel, Switzerland
  • Laura Schwander
    Pharma Research and Early Development, F. Hoffmann-LaRoche Ltd., Basel, Switzerland
  • Carolin Willburger
    Pharma Research and Early Development, F. Hoffmann-LaRoche Ltd., Basel, Switzerland
  • William Riboulet
    F. Hoffmann LaRoche AG, Basel, Switzerland
  • Wilbert Vermeij
    Prinses Maxima Center for Pediatric Oncology, Utrecht, Netherlands
  • Jan HJ Hoeijmakers
    Erasmus MC, Rotterdam, Netherlands
    Prinses Maxima Center for Pediatric Oncology, Utrecht, Netherlands
  • Richard H Foxton
    Pharma Research and Early Development, F. Hoffmann-LaRoche Ltd., Basel, Switzerland
  • Ashwath Jayagopal
    Pharma Research and Early Development, F. Hoffmann-LaRoche Ltd., Basel, Switzerland
  • Ulrich F O Luhmann
    Pharma Research and Early Development, F. Hoffmann-LaRoche Ltd., Basel, Switzerland
  • Footnotes
    Commercial Relationships   Faye Drawnel, F. Hoffmann LaRoche AG (E); Olivia O'Leary, F. Hoffmann LaRoche AG (E); Tabea Grossenbacher, F. Hoffmann LaRoche AG (E); Laura Schwander, F. Hoffmann LaRoche AG (E); Carolin Willburger, F. Hoffmann LaRoche AG (E); William Riboulet, F. Hoffmann LaRoche AG (E); Wilbert Vermeij, F. Hoffmann LaRoche AG (R); Jan Hoeijmakers, F. Hoffmann LaRoche AG (F); Richard Foxton, F. Hoffmann LaRoche AG (E); Ashwath Jayagopal, F. Hoffmann LaRoche AG (E); Ulrich Luhmann, F. Hoffmann LaRoche AG (E)
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 3260. doi:
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      Faye M Drawnel, Olivia O'Leary, Tabea Grossenbacher, Laura Schwander, Carolin Willburger, William Riboulet, Wilbert Vermeij, Jan HJ Hoeijmakers, Richard H Foxton, Ashwath Jayagopal, Ulrich F O Luhmann; Rapid-aging Xpg-/- mice model age-related retinal inflammation. Invest. Ophthalmol. Vis. Sci. 2018;59(9):3260.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Aging remains the major risk factor for the most common blinding disorders including age-related macular degeneration, diabetic retinopathy and glaucoma. Age-related eye diseases are associated with a chronic inflammatory profile, with dysregulation of innate immune processes and upregulation of inflammatory cytokines in the ocular compartment as key hallmarks of disease. Currently, little is known about the specific processes and molecular pathways that underlie age-related changes, which may also contribute to disease in the retina and RPE-choroid. In order to identify such processes in a tractable time frame, we chose to examine the ocular phenotype of a mouse model of monogenetic progeroid syndrome, Xpg-knockout mice (Xpg-/-). This model shows an accelerated aging phenotype due to underlying DNA damage and genotoxic stress, as the mice lack a key exonuclease required for transcription-coupled DNA repair. Consequently, the mice have a short lifespan and develop age-related hepatic changes and neurodegenerative brain pathology due to accumulation of nuclear DNA damage.

Methods : Xpg-/- mice show a fast aging phenotype and hence were studied at 4, 7 and 12-14 weeks. Phenotypic characterization relative to wildtype littermates was conducted by electroretinography (ERG), optical coherence tomography (OCT) and autofluorescence fundus imaging by scanning laser ophthalmoscopy in vivo, and by immunohistological and protein analyses ex vivo.

Results : Ex vivo assessment of Xpg-/- mice revealed progressive accumulation of myeloid cells in the subretinal space, an increased degree of Müller- and micro-gliosis in the retina and progressive RPE pathology. Multiplex immunoassay of ocular fluid from 12-14 weeks old Xpg-/- mice showed upregulation of inflammatory cytokines and chemokines CCL-2, CCL-5, CXCL1 and G-CSF.

Conclusions : These data suggest that in Xpg-/- mice accelerated aging is associated with early activation of the innate immune system in the retina and confirm that the model displays an ocular phenotype with inflammatory and degenerative features consistent with human retinal diseases. Xpg-/- mice may represent an opportunity to test immune-modulatory therapies for the attenuation of retinal degeneration in age-related retinal diseases within a tractable timeframe.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.

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