May 2008
Volume 49, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2008
Long-Term Effects of Combination versus Single Agent Therapy Targeting Amyloid-ß in Glaucoma Treatment
Author Affiliations & Notes
  • L. Guo
    Institute of Ophthalmology, London, United Kingdom
    Glaucoma & Retinal Neurodegeneration Res,
  • T. E. Salt
    Institute of Ophthalmology, London, United Kingdom
    Visual Sciences,
  • W. Cheung
    Institute of Ophthalmology, London, United Kingdom
    Glaucoma & Retinal Neurodegeneration Res,
  • F. RussoMarie
    INSERM, Paris, France
  • M. E. Cheetham
    Institute of Ophthalmology, London, United Kingdom
    Molecular Neurodegeneration,
  • S. E. Moss
    Institute of Ophthalmology, London, United Kingdom
    Cell Biology,
  • F. W. Fitzke
    Institute of Ophthalmology, London, United Kingdom
    Visual Sciences,
  • M. F. Cordeiro
    Institute of Ophthalmology, London, United Kingdom
    Glaucoma & Retinal Neurodegeneration Res,
    St Mary's NHS Trust, Western Eye Hospital, London, United Kingdom
  • Footnotes
    Commercial Relationships  L. Guo, None; T.E. Salt, None; W. Cheung, None; F. RussoMarie, None; M.E. Cheetham, None; S.E. Moss, None; F.W. Fitzke, None; M.F. Cordeiro, None.
  • Footnotes
    Support  Wellcome Trust
Investigative Ophthalmology & Visual Science May 2008, Vol.49, 5495. doi:https://doi.org/
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      L. Guo, T. E. Salt, W. Cheung, F. RussoMarie, M. E. Cheetham, S. E. Moss, F. W. Fitzke, M. F. Cordeiro; Long-Term Effects of Combination versus Single Agent Therapy Targeting Amyloid-ß in Glaucoma Treatment. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5495. doi: https://doi.org/.

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

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Abstract

Purpose: : We have recently demonstrated that amyloid-ß (Aß) is associated with glaucoma, and that its targeting significantly reduces retinal ganglion cell (RGC) apoptosis in experimental glaucoma. In this study, we have investigated long-term effects of combination verses single agent therapy targeting Aß in glaucoma treatment.

Methods: : Using a rat model of chronic ocular hypertension (OHT), we intravitreally administered single, dual and triple combinations of three different agents targeting Aß pathway at the time of surgical IOP elevation: monoclonal anti-Aß antibody (Aßab (0.5mg/ml, n=5), Congo red (CR, 1.46mg/ml, n=5), ß-secretase inhibitor (ßSI, 10µg/ml, n=5), and vehicle control (n=5). For combination therapy (Triple (Aßab+CR+ßSI), Dual1(Aßab+CR), Dual2 (Aßab+ßSI)) individual treatments were combined with the same doses as in the monotherapy. Animals were imaged for RGC apoptosis at 3, 8 and 16 weeks after IOP elevation using our novel DARC (Detection of Apoptosing Retinal Cells) imaging method and then sacrificed for histology.

Results: : All combination therapies targeting different aspects of Aß pathway showed a reduction of RGC apoptosis at 3, 8 and 16 weeks compared to vehicle control although this was only significant at 3 weeks (p<0.05). Triple therapy was found to be the most effective combination regimen in prevention of RGC death, consistently reducing levels of RGC apoptosis by 84%, 66% and 75% at 3, 8 and 16 weeks compared to 74%, 58% and 51% with Aßab alone (which was the most effective monotherapy), although this effect was only statistically significant at 3 weeks (p<0.05). Dual therapies showed no statistical difference from Aßab alone or control at all the time points observed.

Conclusions: : Combination treatments targeting different stages of amyloid-ß pathway appear more effective than single agent treatment in reducing RGC apoptosis in experimental glaucoma. However, this is only significant at 3 weeks after IOP elevation. We attribute the lack of a long-term effect to the fact that treatment was only given as a single application at the time of IOP elevation. We plan to shortly report on the effects of repeated applications of combination therapy.

Keywords: neuroprotection • apoptosis/cell death • pathology: experimental 
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