Poster at Neuroscience 2004, San Diego, 23-27 October 2004

Immune modulation: A Novel Treatment for Ischemic Stroke

Geffen Y¹, Nyska A², Kipnis J³, Ziv Y³, Smirnov I¹ ,Shpilman S¹, Vertkin I ¹,Kimron M¹, Hecht T⁴, Reymann K⁴, M, Schwartz M³, Yoles E¹ .

¹Proneuron Biotechnologies, Ness –Ziona 74101, Israel

²Lab. Expt. Path., Natl. Inst. Env. Health Sci., NIH, PO Box 12233, NC 27709, USA

³Dept. Neurobiol, Weizmann Inst. Sci., Rehovot, 76100, Israel

⁴FAN gGmbH, 39120, Magdeburg, Germany

In stroke, as in many neurodegenerative disorders, the immune response evoked by injury mediates degenerative and repair processes. Recently, it was shown that activation of the autoimmune response is part of a physiological repair mechanism that operates following CNS damage. Moreover, an appropriately controlled boost to the immune response, by vaccination or transfer of CNS-reactive T-cells, was shown to enhance functional recovery. PN277 is a synthetic copolymer that boosts the immune response to CNS injury. In vitro studies revealed that PN277 attenuates the suppressor activity of naturally occurring CD4+CD25+ regulatory T-cells. In vivo experiments showed that PN277 increases resistance of CNS neurons following exposure to toxic glutamate. We examined the effect of PN277 in a rat model of permanent middle cerebral artery occlusion (MCAO). A single injection of PN277, administered 24 hours post MCAO, resulted in significantly improved neurological outcomes measured during 6 weeks. using Morris Water Maze (visible platform task) evaluations 4 weeks post MCAO showed that whereas untreated rats behaved abnormally, PN277-treated rats behaved normally, like sham-operated rats. PN277 had no effect on infarct volume, but enhanced survival of hippocampal neurons, and cell proliferation at the subventricular zone and the dentate gyrus, areas shown to contain neuronal progenitor cells. Histopathology indicated that 4 weeks after PN277 injection there is no significant residual inflammation, and the degree of gliosis is comparable to control MCAO rats. PN277 may be used as a safe, non-destructive, immune-based therapy that enhances tissue repair and gives long-lasting functional and behavioural recovery, even when given as late as 24 hours after stroke.