Preparing for IND-enabling safety studies for a potent and efficient neuroprotective drug.

项目总结/摘要 Ca 2 +/钙调蛋白依赖性蛋白激酶II（CaMKII）是两种相反形式的NMDA的中心介体。 受体（NMDAR）依赖性突触可塑性：长时程增强（LTP）和抑制（LTD）。 脑缺血期间NMDAR的病理性过度刺激引起兴奋性毒性神经元细胞死亡， 我们最近发现CaMK Ⅱ也介导了全脑缺血（GCI）后的神经元损伤。 重要的是，体内注射我们优化的CaMKII抑制剂（tatCN 19 〇）提供了显著的神经保护作用。 在GCI之后，在最接近模拟人体状况的模型中：心肺复苏（CPR） 在小鼠心脏骤停后或在猪心室纤颤后（未发表）。CaMKII抑制（i）为 在这些条件的高度临床相关的时间点（CPR后30分钟）进行;（ii）有效， 与当前的护理标准（治疗性低温）结合;和（iii）不仅保护神经元 细胞死亡，但也从长期持久的功能障碍，在LTP中看到的存活的神经元。 为了能够在人体中进行测试，该SBIR项目将进行成功IND所需的研究， FDA的申请，特别是包括完整的毒理学和安全药理学。这项I期 建议，我们将首先完成最后的治疗相关的生化表征的一块， 抑制剂.然后，我们将启动IND申请所需的PK研究（首先需要 用于检测受试物种血清中我们的抑制剂的方法的验证）。

Project Summary/Abstract The Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a central mediator of two opposing forms of NMDA- receptor (NMDAR)-dependent synaptic plasticity: long-term potentiation (LTP) and depression (LTD). Pathological overstimulation of NMDARs during cerebral ischemia causes excitotoxic neuronal cell death, and we have recently shown that CaMKII also mediates the neuronal damage after global cerebral ischemia (GCI). Importantly, in vivo injection of our optimized CaMKII inhibitor (tatCN19o) provided significant neuroprotection after GCI in models that closely mimic the most relevant human conditions: cardiopulmonary resuscitation (CPR) after cardiac arrest in mice or after ventricular fibrillations in pig (unpublished). CaMKII inhibition (i) was conducted at a highly clinically relevant timepoint for these conditions (30 min after CPR); (ii) was effective in conjunction with current standard of care (therapeutic hypothermia); and (iii) protected not only from neuronal cell death, but also from the long-lasting functional impairments in LTP that are seen in the surviving neurons. In order to enable testing in humans, this SBIR project will conduct the studies required for a successful IND- application with the FDA, specifically including complete toxicology and safety pharmacology. In this phase I proposal, we will first complete the final therapeutically relevant piece of biochemical characterization of the inhibitor. Then, we will initiate the PK studies that are required for an IND application (which first requires a validation of a method for detection of our inhibitor in serum of the tested species).