March 2012
Volume 53, Issue 14
Free
ARVO Annual Meeting Abstract  |   March 2012
AL-78898A Inhibits Complement Deposition in a Primate Light Damage Model
Author Affiliations & Notes
  • Robert J. Collier
    Retina Discovery Research, Novartis Institutes for Biomedical Research - FTW, Fort Worth, Texas
  • Sherry Smith
    Retina Discovery Research, Novartis Institutes for Biomedical Research - FTW, Fort Worth, Texas
  • Hayden Hoang
    Retina Discovery Research, Novartis Institutes for Biomedical Research - FTW, Fort Worth, Texas
  • Elizabeth Martin
    Retina Discovery Research, Novartis Institutes for Biomedical Research - FTW, Fort Worth, Texas
  • Yu Wang
    Retina Discovery Research, Novartis Institutes for Biomedical Research - FTW, Fort Worth, Texas
  • Li Zhu
    Retina Discovery Research, Novartis Institutes for Biomedical Research - FTW, Fort Worth, Texas
  • Richard Ornberg
    Retina Discovery Research, Novartis Institutes for Biomedical Research - FTW, Fort Worth, Texas
  • Carmelo Romano
    Retina Discovery Research, Novartis Institutes for Biomedical Research - FTW, Fort Worth, Texas
  • Footnotes
    Commercial Relationships  Robert J. Collier, Novartis Institutes for Biomedical Research (E); Sherry Smith, Novartis Institutes for Biomedical Research (E); Hayden Hoang, Novartis Institutes for Biomedical Research (E); Elizabeth Martin, Novartis Institutes for Biomedical Research (E); Yu Wang, Novartis Institutes for Biomedical Research (E); Li Zhu, Novartis Institutes for Biomedical Research (E); Richard Ornberg, Novartis Institutes for Biomedical Research (E); Carmelo Romano, Novartis Institutes for Biomedical Research (E)
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science March 2012, Vol.53, 5362. doi:
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      Robert J. Collier, Sherry Smith, Hayden Hoang, Elizabeth Martin, Yu Wang, Li Zhu, Richard Ornberg, Carmelo Romano; AL-78898A Inhibits Complement Deposition in a Primate Light Damage Model. Invest. Ophthalmol. Vis. Sci. 2012;53(14):5362.

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

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Abstract

Purpose: : Increased risk for development of AMD has been associated with modifications in complement related genes (C2, C3, CFB and CFH). The purpose of this study was to evaluate the role of complement activation in light-exposed retinas and determine if complement inhibition can prevent complement deposition in the retina.

Methods: : Two days prior to light exposure, cynomologous monkeys received an intravitreal injection (100 μL) of AL-78898A (0.15 - 2.1 mgs), a C3 inhibitor. NHPs were exposed to light for 30 min. Forty-eight hours after light exposure tissues were collected for light microscopy and immunohistochemistry (C1q, C3, Factor B, Factor H and membrane attack complex (MAC)). MicroVue EIA kits (Quidel) for C3a-desArg and sC5b-9 were used to quantify activated complement in retina and choroid/RPE samples.

Results: : Two days after light exposure, RPE damage and diffuse pyknotic photoreceptor nuclei were observed. C1q expression was not observed while C3, FB, FH and MAC expression was present over the choriocapillaris, RPE, inner and outer segments and ONL in light exposed retinal regions. Retinal C3a and sC5b-9 levels and RPE/ choroid sC5b-9 levels were significantly higher in vehicle dosed eyes compared to normal eyes. C3a levels were not significantly elevated in light exposed RPE/ choroid samples. Treatment with AL-78898A significantly reduced the light-induced elevation of retinal C3a (0.150 - 2.1 mg) and sC5b-9 (0.35, 0.525 and 2.1 mg) and RPE/ choroid sC5b-9 (0.525 - 2.1 mg) complement levels measured in this model.

Conclusions: : Visible-light exposure results in activation of the alternative complement pathway (positive C3 expression, negative C1q expression). Treatment with AL-78898A significantly reduced the light-induced elevation of complement levels measured in this model and demonstrates the potential utility of a C3 inhibitor for treatment of AMD.

Keywords: radiation damage: light/UV • age-related macular degeneration • immunomodulation/immunoregulation 
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