NanO2 as a Cerebroprotectant in a tMCAO Stroke Model in Mice

项目摘要/摘要 在美国，中风每年影响超过795,000名患者，导致大约140,000人死亡，是最大的单一中风 美国长期医疗费用的原因。大约87%的中风是缺血性的，其中40%是大面积的 血管闭塞(LVO)。急性缺血性中风(AIS)可以通过恢复血液流动来治疗，例如使用血栓- 为符合条件的患者提供药物t-PA。最近，机械性血栓切除术(MT)已成为治疗的标准 治疗左心室闭塞症。由于MT是一种专门的程序，多达60%的血栓切除患者首先在辐条上进行评估 医院，然后转送到中心医院进行MT。患者从辐条转移到的持续时间 集线器是可变的，可能超过几个小时。使用tPA再灌流也需要时间，通常需要几个小时 为获得足够的血流量所需的时间。一种在高危区域内维持氧合的安全药物 在AIS中可以保存组织直到达到再灌流，从而增加再灌流治疗的有效性。 NuvOx Pharma正在开发一种新的氧疗药物--NanO2TM(2%w/vol十二氟戊烷乳剂)。在……里面 在中风的多项动物研究中，纳米O2保持了半影区的组织活性并减少了体积 梗死率为85%。在AIS患者的Ib/II期试验中，NanO2在所有剂量水平(0.05、0.10和0.17毫升/公斤)下都是安全的。 间隔90分钟给药3次，证明是有效的。高剂量队列有显著的 在30天和90天时，改良Rankin量表的功能终点与安慰剂相比有改善(P= 0.01和P=0.03)。NuvOx有一个有效的第二阶段试验IND，称为Proven Trial(第二阶段至第二阶段 使用纳米O2为移植途中的LVO患者恢复氧气)。我们假设早期给药的纳米O2 对于AIS来说，患者将保持半影区组织的活性，直到可以再灌注。 NINDS已经开发了中风临床前评估网络(SPAN)计划来寻找神经保护 要带到诊所来的特工。为了使NanO2程序在应用中与这些神经保护剂竞争 对于未来的NIH StrokeNet，NuvOx必须确保我们临床前研究的科学严谨性和可重复性 符合跨度标准。我们的临床前数据很有希望，但缺乏包括老年动物在内的其他 卒中和长期功能结果测量的并存。在此第一阶段的短期租赁权拨款中 应用：我们建议开展纳米O2在短暂性大脑中动脉闭塞中的研究 (TMCAO)小鼠模型的腔内微丝技术。研究将分两个阶段进行。 首先在健康小鼠中建立混杂变量较少的模型，然后在老年进行第二阶段 小鼠和患有共病的小鼠。成功完成这项研究的目标将满足美国国立卫生研究院的要求 为了严密性和重复性，以便纳米O2可以被认为是StrokeNet和 美国国立卫生研究院支持的其他组织。

PROJECT SUMMARY/ABSTRACT Stroke affects more than 795,000 patients per year in the US, kills approximately 140,000 and is the single largest cause of expense for long-term medical care in the US. About 87% of strokes are ischemic, 40% of which are large vessel occlusions (LVO). Acute ischemic stroke (AIS) can be treated by restoring blood flow, e.g. by using the clot- busting drug t-PA for eligible patients. Recently, mechanical thrombectomy (MT) has emerged as standard of care for LVO stroke. As MT is a specialized procedure, up to 60% of thrombectomy patients are first evaluated at spoke hospitals and then transferred to a hub hospital for MT. The duration of time for patient transfer from the spoke to the hub is variable and may be in excess of several hours. Reperfusion with tPA also takes time, usually several hours for adequate blood flow to be obtained. A safe drug which maintained oxygenation within the at-risk region in AIS could preserve the tissue until reperfusion is attained, thereby increasing the utility of reperfusion therapy. NuvOx Pharma is developing a novel oxygen therapeutic, NanO2TM (2% w/vol dodecafluoropentane emulsion). In multiple animal studies in stroke, NanO2 maintained the tissue viability in the penumbra and reduced the volume of infarct by 85%. In a Phase Ib/II trial in AIS patients, NanO2 was safe at all dose levels (0.05, 0.10 & 0.17 mL/kg) administered 3 times 90 minutes apart and was shown to be efficacious. The high dose cohort had a significant improvement compared to placebo in the functional end-point of the modified Rankin scale at 30 and 90 days (P = 0.01 and P=0.03, respectively). NuvOx has an active IND for a Phase II trial called the PROVEN trial (Phase II to Restore Oxygen in LVO patients En Route for MT using NanO2). We hypothesize that early administration of NanO2 to AIS patients will maintain viability of tissue in the penumbra until reperfusion can be attained. The NINDS has developed the Stroke Preclinical Assessment Network (SPAN) program to find neuroprotective agents to bring to the clinic. To make the NanO2 program competitive with these neuroprotectants in an application to NIH StrokeNet in the future, NuvOx must ensure the scientific rigor and reproducibility of our preclinical studies match the standard of SPAN. Our preclinical data is promising, but lacks the inclusion of aged animals, other comorbidities for stroke and long-term functional outcome measurements. In this Phase I STTR grant application, we propose to conduct studies of NanO2 in a transient middle cerebral artery occlusion (tMCAO) mouse model using the intraluminal filament technique. The study will be conducted in two phases, first in healthy mice to establish the model with less confounding variables followed by a second phase in aged mice and mice with comorbidities. Successful completion of the Aims of this study will fulfill the NIH’s requirement for rigor and reproducibility so that NanO2 can be considered as a candidate for clinical trials in StrokeNet and other organizations supported by NIH.