June 2022
Volume 63, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2022
THR-687, a potent pan-RGD integrin antagonist, protects against retinal vascular permeability, inflammation and reactive gliosis in the diabetic rat
Author Affiliations & Notes
  • Tine Van Bergen
    Oxurion NV, Leuven, Belgium
  • Astrid De Vriese
    Oxurion NV, Leuven, Belgium
  • Bart Jonckx
    Oxurion NV, Leuven, Belgium
  • Kelly Vanhulst
    Oxurion NV, Leuven, Belgium
  • Marc Vanhove
    Oxurion NV, Leuven, Belgium
  • Michaël Porcu
    Oxurion NV, Leuven, Belgium
  • Elke Vermassen
    Oxurion NV, Leuven, Belgium
  • Philippe Barbeaux
    Oxurion NV, Leuven, Belgium
  • Alan W Stitt
    Oxurion NV, Leuven, Belgium
    Queen's University Belfast, Belfast, Belfast, United Kingdom
  • Footnotes
    Commercial Relationships   Tine Van Bergen Oxurion NV, Code E (Employment); Astrid De Vriese Oxurion NV, Code E (Employment); Bart Jonckx Oxurion NV, Code E (Employment); Kelly Vanhulst Oxurion NV, Code E (Employment); Marc Vanhove Oxurion NV, Code E (Employment); Michaël Porcu Oxurion NV, Code E (Employment); Elke Vermassen Oxurion NV, Code E (Employment); Philippe Barbeaux Oxurion NV, Code E (Employment); Alan Stitt Oxurion NV, Code E (Employment)
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2022, Vol.63, 2306. doi:
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      Tine Van Bergen, Astrid De Vriese, Bart Jonckx, Kelly Vanhulst, Marc Vanhove, Michaël Porcu, Elke Vermassen, Philippe Barbeaux, Alan W Stitt; THR-687, a potent pan-RGD integrin antagonist, protects against retinal vascular permeability, inflammation and reactive gliosis in the diabetic rat. Invest. Ophthalmol. Vis. Sci. 2022;63(7):2306.

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

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Abstract

Purpose : Targeting RGD-binding integrins can affect multiple disease hallmarks such as vascular leakage, inflammation, angiogenesis and fibrosis. Therefore, an RGD-integrin inhibitor may have therapeutic benefit for various retinal disorders. In this study, we investigated the therapeutic potential of THR-687, a potent pan-RGD integrin antagonist, in the streptozotocin (STZ)-induced diabetes rat model.

Methods : Following STZ-induced diabetes, different doses of THR-687 (6.7, 16.7 or 75 µg/eye) or its vehicle were administered via 3 consecutive intravitreal injections in both eyes (with 1-week interval, n=7 rats/group). Untreated, non-diabetic rats served as controls (n=5 rats). At 4 weeks after diabetes-induction, the effect of THR-687 was investigated by histological analysis for retinal vascular leakage (using the tracer FITC-BSA), for inflammatory cell activation (Iba1 immunoreactivity) and Müller cell gliosis (vimentin immunoreactivity). Statistical analysis was performed with a one-way analysis of variance using a Bonferroni multiple comparison test.

Results : THR-687 reduced diabetes-induced increases in retinal permeability versus vehicle in a dose-dependent manner. The highest dose (75 µg/eye) completely prevented vascular leakage (p<0.001) while the mid dose (16.7 µg/eye) significantly decreased this pathology by 34 ± 21% (p<0.05) and the low dose (6.7 µg/eye) had no effect. All doses of THR-687 also significantly reduced the number of inflammatory cells, as compared to vehicle. Indeed, a reduction of 57 ± 12% was seen after administration of the highest dose (p<0.01), a decrease of 43 ± 19% for the mid dose (p<0.05) and the low dose induced a reduction of 51 ± 13% (p<0.05). The highest dose of THR-687 also reduced the diabetes-induced increase in vimentin expression within the Müller cells back to baseline (p<0.05 versus vehicle), whereas no significant differences following injections of the mid or low dose were observed.

Conclusions : RGD-integrin antagonism using THR-687 potently inhibits vascular permeability, inflammation and gliosis induced by STZ in the diabetic rat retina. Given its broad mode of action, THR-687 is a promising drug candidate for the treatment of vision-threatening retinal pathologies and is currently in a phase 2 clinical trial in diabetic macular edema patients (INTEGRAL - NCT05063734).

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.

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