A preclinical randomized multicenter trial of anti-IL-17A treatment for acute ischemic stroke

Gelderblom, M.; Koch, S.; Strecker, J. K.; Joergensen, C.; Garcia-Bonilla, L.; Ludewig, P.; Bernreuther, C.; Pinnschmidt, H.; Arumugam, T. V.; Thomalla, G.; Faber, C.; Sedlacik, J.; Gerloff, C.; Minnerup, J.; Clausen, B. H.; Anrather, J.; Magnus, T.

doi:10.1101/2021.09.29.462381

bioRxiv · 10.1101/2021.09.29.462381

A preclinical randomized multicenter trial of anti-IL-17A treatment for acute ischemic stroke

Gelderblom, M.·Koch, S.·Strecker, J. K.·Joergensen, C.·Garcia-Bonilla, L.·Ludewig, P.·Bernreuther, C.·Pinnschmidt, H.·Arumugam, T. V.·Thomalla, G.·Faber, C.·Sedlacik, J.·Gerloff, C.·Minnerup, J.·Clausen, B. H.·Anrather, J.·Magnus, T.

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Abstract

Multiple consensus statements have called for preclinical randomized controlled trials (pRCT) to improve translation in stroke research. Here, we investigated the efficacy of IL-17A neutralizing antibodies in a multicentric pRCT using a murine stroke model. C57/Bl.6 mice were subjected to transient middle cerebral artery occlusion (tMCAO). Mice were randomly allocated (1:1). Either anti-IL-17A (500 {micro}g) or isotype antibody (500 {micro}g) were administered 1 h after tMCAO. Primary analysis of infarct volumes was done by MRI after three days. Secondary analysis included mortality, neurological score, neutrophil infiltration and the impact of the gut microbiome on treatment effects. Out of 136 mice, 109 mice were included in the analysis. Mixed model analysis revealed that the IL-17A neutralization significantly reduced infarct sizes (anti IL-17A: 61.77 {+/-} 31.04 mm3; IgG control: 75.66 {+/-} 34.79 mm3; p=0.01). Secondary outcome measures showed a decrease in mortality (Hazard Ratio=3.43, 95% CI = 1.157 - 10.18; p=0.04) and neutrophil invasion into ischemic cortices. There was no difference in the neurological score. The analysis of the gut microbiome showed significant differences between centers. Taken together, this is the first positive pRCT in an ischemia reperfusion model. It suggests IL-17A neutralization as a potential target in stroke.

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Gelderblom, M., Koch, S., Strecker, J. K., Joergensen, C., Garcia-Bonilla, L., Ludewig, P., Bernreuther, C., Pinnschmidt, H., Arumugam, T. V., Thomalla, G., Faber, C., Sedlacik, J., Gerloff, C., Minnerup, J., Clausen, B. H., Anrather, J., Magnus, T.. 2021-10-01. A preclinical randomized multicenter trial of anti-IL-17A treatment for acute ischemic stroke. https://doi.org/10.1101/2021.09.29.462381

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