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

为一种强效且高效的神经保护药物进行 IND 安全性研究做准备。

基本信息

批准号：
10257462
负责人：
Robyn Goforth
金额：
$ 49.61万
依托单位：
NEUREXIS THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-24 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10257462
关键词：
Acute Address Adverse event Affinity American Anatomy Animal Model Asphyxia Behavioral Binding Biochemical Biological Blood - brain barrier anatomy Brain region Cardiac Cardiopulmonary Resuscitation Cells Cerebral Ischemia Cessation of life Characteristics Clinical Colorado Combined Modality Therapy Detection Dissociation Dose Drowning Drug Kinetics Family suidae Freeze Drying Heart Arrest Hospitalization Hour Human Impaired cognition Impairment Injectable Injections Instruction Intellectual Property Investments Kinetics Learning Legal patent Long-Term Potentiation Mediating Mediator of activation protein Memory Mental Depression Methods Modeling Mus Mutant Strains Mice N-Methyl-D-Aspartate Receptors Neurons Neuroprotective Agents Pathologic Patients Peptides Pharmacology Pharmacology and Toxicology Phase Phosphotransferases Plasma Powder dose form Preparation Property Rattus Research Residual state Retrograde amnesia Rodent Safety Saline Sampling Series Serum Site Small Business Innovation Research Grant Structure Synaptic plasticity Testing Therapeutic Time Toxicology Universities Validation Ventricular Fibrillation Water base biophysical techniques calmodulin-dependent protein kinase II clinically relevant commercialization comparative detection method excitotoxicity experience functional disability in vivo inhibitor/antagonist kinase inhibitor natural hypothermia neuron loss neuroprotection research clinical testing safety study standard of care success therapeutic lead compound tool

项目摘要

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).

项目摘要/摘要 Ca2+/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：长期增强（LTP）和抑郁（LTD）。脑缺血期间NMDAR的病理过度刺激导致兴奋性神经元细胞死亡，并我们最近表明，CAMKII还介导了全球脑缺血（GCI）后的神经元损伤。重要的是，在体内注射我们优化的CAMKII抑制剂（TATCN19O）提供了重要的神经保护作用在与最相关的人类条件紧密模仿的模型中GCI之后：心肺复苏（CPR）在小鼠心脏骤停或猪心室纤颤后（未发表）。 camkii抑制（i）是在这些条件下在高度临床相关的时间点上进行（CPR后30分钟）；（ii）有效与当前护理标准（治疗性体温过低）的结合；（iii）不仅保护神经元细胞死亡，也来自LTP中持续的功能障碍，这些功能障碍在幸存的神经元中看到。为了在人类中进行测试，该SBIR项目将进行成功的研究所需的研究使用FDA的应用，特别是包括完整的毒理学和安全药理学。在这个阶段第一提案，我们将首先完成最终的治疗相关的生化特征抑制剂。然后，我们将启动IND应用所需的PK研究（首先需要一个在测试物种的血清中检测我们抑制剂的方法的验证）。