Testing the Lipoxygenase Inhibitor BPN - 27332 as acute phase stroke treatment in the SPAN network

The goal of this project is to evaluate a novel inhibitor of the 12/15 lipoxygenase (12/15-LOX) enzyme in preclinical rodent models of ischemic stroke within the SPAN network. To this end, BPN-27332 will be tested in comparison with other preclinical stroke treatments under rigorous conditions in multiple laboratories. 12/15-LOX has been shown to be up-regulated in the ischemic peri-infarct area in both rodents and humans. It contributes to both neuronal cell death, as well as to weakening of the blood – brain barrier and edema formation. Alox15(-/-) mice in which the gene encoding 12/15-LOX has been knocked out, are protected in models of transient focal ischemia. Through the NIH Blueprint Neurotherapeutics Program we have developed BPN-27332, a novel and highly selective inhibitor of 12/15-LOX. In a mouse model of transient focal ischemia, BPN-27332 reduces infarct size when given in the acute phase. Protection is long lasting, with significant behavioral benefits still seen four weeks after the experimental stroke with excellent ADME and PK/PD properties. We now propose to test BPN-27332 in a blinded fashion in comparison with vehicle, but also with other treatment modalities. In Aim 1, the compound is subjected to rigorous quality control measures, including verification of identity and purity by HPLC and mass spectrometry and in vitro efficacy testing. In Aim 2, the compound will be shipped to the Coordinating Center for distribution to the testing sites, where BPN-27332 will be extensively tested in rodent models of ischemic stroke. Successful completion of these studies will ready BPN-27332 for clinical trials in human patients, which will hopefully lead to a much needed new treatment option for patients with ischemic strokes.