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

项目摘要/摘要 钙/钙调蛋白依赖的蛋白激酶II(CaMKII)是两种截然相反形式的NMDA的中枢调节因子。 受体(NMDAR)依赖的突触可塑性：长时程增强(LTP)和抑制(LTD)。 脑缺血时NMDAR的病理性过度刺激导致兴奋性神经细胞死亡，并 我们最近发现CaMKII也参与了全脑缺血(GCI)后神经元的损伤。 重要的是，体内注射我们优化的CaMKII抑制剂(TalCN19o)提供了显著的神经保护 在GCI之后，在模拟最相关的人类状况的模型中：心肺复苏(CPR) 在小鼠心脏骤停后或在猪的心室颤动后(未发表)。CaMKII抑制(I)为 在这些情况下在高度临床相关的时间点(CPR后30分钟)进行；(Ii)在 与目前的护理标准相结合(治疗性低温)；和(Iii)不仅保护神经元免受 细胞死亡，也是由于存活神经元中LTP的长期功能损伤所致。 为了在人体上进行测试，这个SBIR项目将进行成功的IND所需的研究- 向FDA申请，特别是包括完整的毒理学和安全药理学。在此阶段I 提案，我们将首先完成最后一段与治疗相关的生化表征 抑制剂。然后，我们将启动IND应用程序所需的PK研究(首先需要 检测受试物种血清中我们的抑制物的方法的有效性)。

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conditions: cardiopulmonary resuscitation (CPR) after cardiac arrest in mice or after ventricular fibrillations in pig (unpublished).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).