June 2013
Volume 54, Issue 15
Free
ARVO Annual Meeting Abstract  |   June 2013
Soluble guanylate cyclase: an emerging therapeutic target in open angle glaucoma
Author Affiliations & Notes
  • Emmanuel Buys
    Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, MA
  • Yu-Chieh Ko
    Ophthalmology, Schepens Eye Research Institute, Boston, MA
  • Clemens Alt
    Wellman Center for Photomedicine and Center for Systems Biology, Massachusetts General Hospital, Boston, MA
  • Haiyan Gong
    Ophthalmology, Boston University School of Medicine, Boston, MA
  • Peter Brouckaert
    VIB Department of Molecular Biomedical Research, Ghent University, Ghent, Belgium
  • Janey Wiggs
    Ophthalmology, Massachusetts Eye and Ear Infirmary, Boston, MA
  • Meredith Gregory-Ksander
    Ophthalmology, Schepens Eye Research Institute, Boston, MA
    Ophthalmology, Massachusetts Eye and Ear Infirmary, Boston, MA
  • Louis Pasquale
    Ophthalmology, Massachusetts Eye and Ear Infirmary, Boston, MA
    Channing Division of Network Medicine, Brigham and Women’s Hospital, Boston, MA
  • Kenneth Bloch
    Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, MA
    Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston, MA
  • Bruce Ksander
    Ophthalmology, Schepens Eye Research Institute, Boston, MA
    Ophthalmology, Massachusetts Eye and Ear Infirmary, Boston, MA
  • Footnotes
    Commercial Relationships Emmanuel Buys, None; Yu-Chieh Ko, None; Clemens Alt, None; Haiyan Gong, None; Peter Brouckaert, None; Janey Wiggs, None; Meredith Gregory-Ksander, None; Louis Pasquale, None; Kenneth Bloch, None; Bruce Ksander, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2013, Vol.54, 1609. doi:
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      Emmanuel Buys, Yu-Chieh Ko, Clemens Alt, Haiyan Gong, Peter Brouckaert, Janey Wiggs, Meredith Gregory-Ksander, Louis Pasquale, Kenneth Bloch, Bruce Ksander; Soluble guanylate cyclase: an emerging therapeutic target in open angle glaucoma. Invest. Ophthalmol. Vis. Sci. 2013;54(15):1609.

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

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Abstract

Purpose: Primary open angle glaucoma (POAG) is a leading cause of blindness. Available therapies offer incomplete protection. The molecular signaling involved in the pathogenesis of POAG remains unknown. Here, we identify the nitric oxide (NO) receptor soluble guanylate cyclase (sGC) as a key enzyme in the etiology of POAG, using a novel murine gene knockout model and genetic data from a subgroup of POAG patients.

Methods: Female wild-type (WT) mice and mice lacking the α1 subunit of sGC (sGCα1-/-) were studied. Thickness of the retinal nerve fiber layer (RNFL) was measured via spectral domain optical coherence tomography (SD-OCT). Retinal ganglion cells (RGCs) and optic nerve axons were detected histochemically and counted. Morphology of the iridocorneal angle was examined by light microscopy, ultrasound biomicroscopy, and SD-OCT. Intraocular pressure (IOP) was measured serially with a TonoLab-Tonometer. Retinal arterial function was assessed via in vivo laser ophthalmoscopy. POAG cases and controls from the Glaucoma Genes and Environment (GLAUGEN) study were studied for their association with genetic variants in the sGC locus.

Results: Age-dependent thinning of the RNFL and loss of RGC’s and optic nerve axons in the context of an open iridocorneal angle was observed in sGCα1-/- but not age-matched WT mice. The optic neuropathy associated with sGCα1-deficiency was accompanied by a modest (~2mmHg) and age-dependent increase in IOP and by retinal artery dysfunction. A candidate gene association study of POAG with paracentral vision loss, a POAG subtype thought to be associated with vascular dysregulation, identified a variant in the locus containing the genes encoding the α1 and β1 subunits of sGC. Together, these results highlight the relevance of sGC (and our animal model) in the pathogenesis of POAG.

Conclusions: This study provides new insights into the pathogenesis and genetics of POAG and represents a paradigm shift in POAG research. Our findings suggest that therapies that do not focus on lowering IOP (e.g. targeting retinal vascular dysfunction) constitute a complementary approach to treating POAG. In addition, our observations unequivocally identify perturbation of a well-characterized signaling pathway (NO-cGMP signaling) as a key mechanism in the etiology of POAG. Identifying sGC as a potential therapeutic target for POAG may inform the clinical development of existing cGMP-elevating therapeutic compounds.

Keywords: 617 nitric oxide • 740 transgenics/knock-outs • 440 candidate gene analysis  
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