Immune modulator treatment, even 24 hours post ischemic stroke in rats, leads to improved neurological outcome

Geffen Y, Kipnis Y*, Smirnov I ,Shpilman S, Vertkin I ,Kimron M, Kazanovsky L, Schwartz M*, Yoles E.
Proneuron Biotechnologies, Ness –Ziona 74101, Israel
*Dept. Neurobiology, The Weizmann Institute of Science, Rehovot, 76100, Israel

The failure of many clinical trials using neuroprotective agents that target a specific pathway of the ischemic cascade emphasizes the need for a new strategy for neuroprotection. Recently, it was shown that activation of the autoimmune response is part of a physiological repair mechanism following CNS damage. Moreover, an appropriately controlled boost to the immune response was shown to enhance functional recovery in the injured CNS.  PN277 is a synthetic copolymer that modulates immune activity, thus boosting the spontaneous repair mechanism evoked by CNS injury. We found that systemic treatment of mice with PN277 resulted in increased neuronal survival relative to control mice following exposure to toxic amounts of glutamate, a major common element in neurodegenerative diseases. We further showed in a permanent middle cerebral artery occlusion (MCAO) model, in rats that single injection of PN277, administered immediately, 6 hours or 24 hours post MCAO, significantly improved neurological outcome measured up to 14 days post occlusion. These results were in line with the reduced weight loss observed in the PN277 treated animals. Administration of PN277 had no effect on infarct volume, but enhanced hippocampus neuron survival. In vitro studies suggest that PN277, by weakening the activity of naturally occurring CD4+CD25+ regulatory T cells, allows recruitment of protective T-cells. PN277 may be used as a unique immune-based therapy that offers long-lasting functional recovery, even when given as late as 24 hours after insult.