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. 2016;2(2):28-33.
Epub 2016 Nov 21.

GSK249320, A Monoclonal Antibody Against the Axon Outgrowth Inhibition Molecule Myelin-Associated Glycoprotein, Improves Outcome of Rodents with Experimental Stroke

Diana Cash  1 , Alanna C Easton  1 , Michel Mesquita  1 , John Beech  1 , Steve Williams  1 , Andrew Lloyd  2 , Elaine Irving  3 , Steven C Cramer  4
Affiliations

GSK249320, A Monoclonal Antibody Against the Axon Outgrowth Inhibition Molecule Myelin-Associated Glycoprotein, Improves Outcome of Rodents with Experimental Stroke

Diana Cash et al. J Neurol Exp Neurosci. 2016.

Abstract

Myelin-associated glycoprotein (MAG) is an inhibitor of axon growth. MAG levels increase after stroke. GSK249320 is a monoclonal antibody that neutralizes MAG-mediated inhibition and so may promote axon outgrowth and improve post-stroke outcomes. The current study tested the hypothesis that GSK249320 initiated 24 hours or 7 days after experimental stroke improves behavioural outcomes. Rats with right middle cerebral artery occlusion for 90 minutes were randomized to receive 6 weeks of intravenous (a) GSK249320 starting 24 hours post-stroke, (b) GSK249320 starting 7 days post-stroke, or (c) vehicle. Behavioral testing was performed over 7 weeks. Serial MRI demonstrated no differences in infarct volume across groups. Animals treated with GSK249320 24 hours post-stroke showed larger increases in Neuroscore (time X group, p = 0.0008) and staircase test (main effect of group, p = 0.0214) as compared to controls, but animals treated 7 days post-stroke showed no significant behavioral benefit. No significant results were found for the sticky tape or cylinder tests. A separate set of animals with experimental stroke received a single intravenous dose of GSK249320 or vehicle at 1 hour, 24 hours, 48 hours or 1 week post-stroke, and immunohistochemistry methods were used to measure GSK249320 distribution; GSK249320 was found in the ipsilesional hemisphere only, the extent of which increased with later times of injection. These data suggest that intravenous GSK249320 penetrates the lesion site and is associated with a small effect on functional outcomes when initiated 24 hours post-stroke and so support the translational potential of this monoclonal antibody as a restorative therapy for patients with stroke.

Keywords: Axon; Plasticity; Recovery; Stroke; Translation; Treatment.

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Figures

Figure 1
Figure 1
Change in Neuroscore over time according to stroke subtype. Mean values are plotted with 95% confidence intervals. [A] Data from animals with a full MCA territory infarct. [B] Data from animals with a subcortical infarct.
Figure 2
Figure 2
Change in staircase test over time according to stroke subtype (square root transform). Mean values are plotted with 95% confidence intervals. [A] Data from animals with a full MCA territory infarct. [B] Data from animals with a subcortical infarct. *specific timepoints where a significant increase was seen in the number of pellets retrieved for MAG 24h animals (subcortical infarct group) as compared to VEH in post hoc testing.
Figure 3
Figure 3
Change in sticky tape test over time according to stroke subtype. Mean values are plotted with 95% confidence intervals. [A] Data from animals with a full MCA territory infarct. [B] Data from animals with a subcortical infarct.
Figure 4
Figure 4
Change in cylinder test over time according to stroke subtype. Mean values are plotted with 95% confidence intervals. [A] Data from animals with a full MCA territory infarct. [B] Data from animals with a subcortical infarct.
Figure 5
Figure 5
Staining for GSK249320 in the ipsilesional hemisphere.
See this image and copyright information in PMC

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