A Novel Neuroprotective Approach for Ischemia

DESCRIPTION (provided by applicant): Ischemia/hypoxia is a significant contributor to neurodegeneration. A typical case is ischemic stroke. Currently, more than 4 million people in the U.S are living with the consequences of stroke. Stroke has become the third leading cause of death in this country, a major cause of long-term disability, and a significant burden on public health worldwide. The clinical significance of cerebral ischemia is compounded by the lack of effective neuroprotective treatments that directly inhibit ischemic neuronal death. Therefore development of novel neuroprotectants is a top priority for the prevention and treatment of ischemic diseases. In phase I of this work we identified a novel class of neuroprotective compounds, the the alpha(N)- heterocyclic carboxaldehyde thiosemicarbazones (HCTs), including PAN-811. Panacea Pharmaceuticals, Inc. has licensed the used of this compound and maintains intellectual property rights for its use in neuroprotective therapy. PAN-811 fully blocks hypoxic and ischemic neuronal cell death at a dose of 1 uM in vitro, and reduces infarct volume by up to 59% in the middle cerebral artery occlusion (MCAo) rat model of stroke. It manifests dual mechanistic functions including both Ca2+ -chelation and free radical-scavenging. Our goal is the development of PAN-811 as a clinically available neuroprotective drug, thus, this phase II grant proposal is aimed at the completion of the requisite preclinical studies. A further pharmacologic study of PAN-811 focusing on its neuroprotective mechanism in reference to necrotic and/or apoptotic cell death is proposed. We will also extend our studies with the MCAo model to optimize the route of administration, compare bolus delivery with infusion, further study dosing effects, and determine the window of therapeutic opportunity. Outcomes will initially be measured by evaluating total infarct volume but will include behavioral testing after more complete establishment of these parameters. PAN-811 is currently in phase II clinical trials for another indication, cancer, by Vion Pharmaceuticals, Inc. As such, much is already known about the human toxicology and pharmacokinetics of PAN-811. If the administration route changes to gain maximum efficacy, the toxicity and pharmacokinetics of PAN-811 will be re-evaluated prior to clinical trial. At the end of the phase II period, we expect to submit an IND application to the FDA to use PAN-811 for the treatment of transient ischemic stroke and initiate phase Ib clinical trials.