Development of Neuroprotective Stroke Thereapy

DESCRIPTION (provided by applicant): The potential of treatment for stroke may be accomplished via acute intervention at the time of the acute stroke or by providing prophylactic neuroprotection to at risk populations. The at risk group includes: 1) co ronary artery bypass surgery patients (who suffer permanent cognitive decline from intra- operative emboli); 2) patients with transient ischemic attacks (which precede stroke in 25-50% of patients with occlusive cerebral vascular disease); and 3) individua ls who have had a previous stroke (recurrent stroke occurs in 25-40% within 5 years). Protection against impending stroke injury can occur through a process known as preconditioning. Distinct stimuli are known to precondition against injury, including brie f periods of ischemia, volatile anesthetics and lipopolysaccharide (LPS). LPS preconditioning occurs through activation of the Toll-like receptor 4 (TLR4), which is a member of a larger family of related Toll-like receptors (TLRs). Such preconditioning ind uces robust protection, however the use of LPS has limitations as a neuroprotectant due to toxicity. We are investigating the potential for additional TLRs to confer tolerance to subsequent ischemic injury. We have discovered that TLR-9 is also a target fo r preconditioning against ischemic injury in the brain. Our studies show that the TLR-9 agonist, CpG ODNs (synthetic oligodeoxynucleotides containing unmethylated CpG motifs) when delivered systemically induces profound neuroprotection in a mouse model of stroke. This is a very promising target as CpG ODNs have been shown to be safe in Phase I/II clinical trials for vaccine therapy. Our GOAL FOR THE PHASE I STTR is to optimize the use of CpG ODN preconditioning as a potential neuroprotectant in patients at high risk of stroke. To improve the therapeutic and translational potential of CpG ODNs as a neuroprotectant, we will define the optimal therapeutic time window and immunomodulatory profile following CpG ODN preconditioning. Aim 1. Determine the time windo w of effectiveness of systemic CpG-induced tolerance to stroke. Aim 2. Determine the temporal profile of white blood cell activation and cytokine modulation in the systemic circulation in response to CpG-induced tolerance to stroke. Protection against impe nding stroke injury can occur through a process known as preconditioning. A recent discovery in our laboratories is that CpG ODNs (synthetic oligodeoxynucleotides containing unmethylated CpG motifs) when delivered systemically induces profound neuroprotect ion in a mouse model of stroke. This is a very promising target as CpG ODNs have been shown to be safe in Phase I/II clinical trials for vaccine therapy. We seek to develop CpG ODNs as a protective stroke therapy.