Osteopontin, a Novel Neuroprotectant in Brain Ischemia

DESCRIPTION (provided by applicant): This is an STTR Phase II proposal to develop the application of a novel neuroprotectant in the treatment of stroke. As in our previous Phase I STTR, this Phase II STTR unites the Stenzel-Poore laboratory and Virogenomics, Inc., a Portland-based genomics and drug discovery company. Here we plan to develop the use of an endogenous 'injury response' protein, osteopontin (OPN) for the treatment of stroke. The fundamental discoveries made during our Phase I STTR were: 1) OPN given at the time of stroke provides marked protection against ischemic injury and 2) cleavage of OPN by thrombin increases its neuroprotective capacity in vitro. These findings motivate us to move forward with OPN as a potential therapeutic and test whether the neuroprotective effect of thrombin-cleaved OPN can be extended to acute stroke injury. Furthermore we propose to expand the therapeutic potential of OPN by determining the efficacy of OPN when given continuously during the acute recovery phase of stroke injury. Finally, we seek to develop a new delivery strategy for OPN using intranasal administration to improve delivery to the brain. The aims are: Aim 1. Determine whether proteolytic fragments of OPN confer neuroprotection against stroke injury. Aim 2. Determine whether continuous OPN administration during the recovery phase of injury improves stroke outcome. Aim 3. Determine whether intranasal delivery of OPN achieves neuroprotection against stroke injury. The immediate goals are to enhance the efficacy and therapeutic potential of OPN as a neuroprotectant in stroke. Improvement of the potency and delivery of OPN in the brain should advance the development of OPN as a treatment in stroke. Moreover, intranasal administration would offer a profound advantage over conventional routes of administration due to improved drug delivery and access to the injured brain.