September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Inactivation of Hif1a rescues rods and cones from degeneration induced by a chronic hypoxia-like response: HIF1A as therapeutic target in AMD?
Author Affiliations & Notes
  • Christian Grimm
    Lab for Retinal Cell Biol, Ophthalmology, University of Zurich, Schlieren / Zurich, Switzerland
  • Maya Barben
    Lab for Retinal Cell Biol, Ophthalmology, University of Zurich, Schlieren / Zurich, Switzerland
  • Divya Ail
    Lab for Retinal Cell Biol, Ophthalmology, University of Zurich, Schlieren / Zurich, Switzerland
  • Brigitt Kast
    Lab for Retinal Cell Biol, Ophthalmology, University of Zurich, Schlieren / Zurich, Switzerland
  • Christian Schori
    Lab for Retinal Cell Biol, Ophthalmology, University of Zurich, Schlieren / Zurich, Switzerland
  • Christina Giger-Lange
    Lab for Retinal Cell Biol, Ophthalmology, University of Zurich, Schlieren / Zurich, Switzerland
  • Stylianos Michalakis
    Center for Integrated Protein Science Munich (CIPSM) and Department of Pharmacy-Center for Drug Research, Ludwig-Maximilians-Universität München, Munich, Germany
  • Marijana Samardzija
    Lab for Retinal Cell Biol, Ophthalmology, University of Zurich, Schlieren / Zurich, Switzerland
  • Footnotes
    Commercial Relationships   Christian Grimm, None; Maya Barben, None; Divya Ail, None; Brigitt Kast, None; Christian Schori, None; Christina Giger-Lange, None; Stylianos Michalakis, None; Marijana Samardzija, None
  • Footnotes
    Support  SNF Grant 31003A_149311
Investigative Ophthalmology & Visual Science September 2016, Vol.57, No Pagination Specified. doi:
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      Christian Grimm, Maya Barben, Divya Ail, Brigitt Kast, Christian Schori, Christina Giger-Lange, Stylianos Michalakis, Marijana Samardzija; Inactivation of Hif1a rescues rods and cones from degeneration induced by a chronic hypoxia-like response: HIF1A as therapeutic target in AMD?. Invest. Ophthalmol. Vis. Sci. 201657(12):.

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      © 2017 Association for Research in Vision and Ophthalmology.

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Abstract

Purpose : Reduced choroidal blood flow and changes in ocular tissues may lead to mild but chronic hypoxic conditions in photoreceptors of the ageing eye. This might trigger the molecular response to hypoxia, possibly contributing to the development of early forms of age-related macular degeneration (AMD). Here we tested whether an artificial activation of hypoxia-inducible transcription factors (HIFs) in rods or cones contributes to age-dependent retinal degeneration and vision loss in mice.

Methods : A chronic hypoxia-like response was triggered in rods of the normal mouse retina or in cones of the R91W;Nrl–/– ‘all-cone’ mouse by the Cre-loxP mediated inactivation of Von Hippel Lindau (Vhl) protein. Additional mice analyzed carried double (Vhl;Hif1a or Vhl;Hif2a) or triple (Vhl;Hif1a;Hif2a) photoreceptor-specific deletions. ERG, OCT and microscopy were used to analyze retinal function and morphology. Transcriptomic analysis, Western blotting and immunofluorescence were applied to investigate the molecular response and potential mechanisms of degeneration.

Results : Inactivation of Vhl in rods or cones resulted in a chronic activation of HIF1A and HIF2A transcription factors and to an increased expression of HIF target genes. Higher expression levels of pyruvate dehydrogenase kinase and lactate dehydrogenase indicated a potential metabolic shift towards anaerobic glycolysis possibly resulting in reduced energy production. Activation of the hypoxic response in photoreceptors induced a progressive retinal degeneration that was rescued by the selective inactivation of Hif1a, but not of Hif2a. Rod-specific inactivation of Hif1a in the normal retina did not affect morphology and function up to 1 year of age.

Conclusions : Chronic activation of a hypoxia-like response in rods or cones leads to a progressive retinal degeneration resulting in loss of vision in the ageing mouse. As inactivation of Hif1a protected the retina, a HIF1A-mediated mechanism is responsible for the degenerative process. Since HIF1A can be safely inactivated in adult photoreceptors of the normal retina, HIF1A provides a potential target for a therapeutic intervention in patients. This hypothesis is currently being tested in pre-clinical trials using AAV-mediated expression of anti-Hif1a shRNA in photoreceptors.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

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