July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
IL-1 receptor modulators protect against oxygen-induced retinopathy
Author Affiliations & Notes
  • Colin Wayne Howe Cheng
    Opthalmology, Hôpital Maisonneuve-Rosemont, Montréal, Quebec, Canada
    Pharmacology & Therapeutics, McGill University, Montreal, Quebec, Canada
  • Azade Geranurimi
    Chemistry, Université de Montréal, Montréal, Quebec, Canada
  • José Carlos Rivera
    Opthalmology, Hôpital Maisonneuve-Rosemont, Montréal, Quebec, Canada
    Pharmacology, CHU Sainte-Justine Research Center, Montréal, Quebec, Canada
  • Isabelle Lahaie
    Opthalmology, Hôpital Maisonneuve-Rosemont, Montréal, Quebec, Canada
  • Christiane Quiniou
    Pharmacology, CHU Sainte-Justine Research Center, Montréal, Quebec, Canada
  • William Lubell
    Chemistry, Université de Montréal, Montréal, Quebec, Canada
  • Sylvain Chemtob
    Opthalmology, Hôpital Maisonneuve-Rosemont, Montréal, Quebec, Canada
    Pharmacology, CHU Sainte-Justine Research Center, Montréal, Quebec, Canada
  • Footnotes
    Commercial Relationships   Colin Cheng, None; Azade Geranurimi, None; José Rivera, None; Isabelle Lahaie, None; Christiane Quiniou, None; William Lubell, None; Sylvain Chemtob, None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 5332. doi:
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      Colin Wayne Howe Cheng, Azade Geranurimi, José Carlos Rivera, Isabelle Lahaie, Christiane Quiniou, William Lubell, Sylvain Chemtob; IL-1 receptor modulators protect against oxygen-induced retinopathy. Invest. Ophthalmol. Vis. Sci. 2018;59(9):5332.

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

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Abstract

Purpose : Previous studies in our lab showed that an allosteric IL-1 receptor modulator named rytvela, was able to prevent oxygen-induced retinopathy (OIR) in a rat model. To better understand the structure-activity relationships of rytvela, we synthesised a panel of its derivatives. We determined the efficacy of these derivatives in vitro, and then selected the most effective derivatives to evaluate their ability to prevent IL-1 activity implicated in vasoobliteration (VO) in the OIR model.

Methods : The efficacies of rytvela and 12 derivatives were evaluated in HEK Blue IL-1β cells by using qPCR to evaluate their inhibition of the expression of inflammatory factors. Controls were treated with either PBS, or IL-1β alone. We then selected four of our best derivatives for testing in OIR. Sprague Dawley pups and their mothers were kept in 80% O2 from P5 to P10, with twice-daily injections of derivatives at a dosage of 2mg/kg/day. At P10, retinas were stained with lectins, flat-mounted and assessed for VO and vascular density. Cryosections were used to assess choroidal thickness. The expression of inflammatory and angiogenic factors was also measured by qPCR. Controls were kept in normoxia (21% O2) or treated with PBS in hyperoxia.

Results : The ability of our derivatives to inhibit the expression of inflammatory factors varied. Rytvela reduced the expression of COX-2 and IL-6, by 81% (p=0.001) and 87% (p=0.0339) respectively. Meanwhile, our most promising derivative, AGU25, had reductions of 97% (p<0.0001) and 98% (p=0.0104); the least efficacious derivative, AGU105, had no effect (p>0.50 for both IL-6 and COX2). After selecting 4 derivatives with the best in vitro results, we also detected variations in their ability to prevent OIR-associated VO. PBS-treated pups had an average retinal VO area of 32.74%. Rytvela reduced this to 24.81% (p=0.0053), while AGU25 had a greater reduction to 21.0% (p=0.0037). However, AGU107, which had performed well in vitro, did not have a significant effect in VO (p=0.848).

Conclusions : Allosteric blockade of the IL-1 receptor is effective in preventing VO in an OIR model. However, we have observed that the results of in vitro screening of IL-1 receptor antagonism do not always translate to in vivo efficacy, as can be seen in derivatives such as AGU107. Nonetheless, we have identified at least one derivative (AGU25) that is promising and should be further studied for eventual drug development.

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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