Preclinical Development of Bone Marrow Mononuclear Cell Therapy for Ischemic Stro

描述(由申请人提供)： 细胞疗法已成为促进缺血性卒中康复的一种新方法。动物中风研究支持来自不同组织的各种类型细胞的安全性和有效性。骨髓细胞可能参与神经损伤后脑修复的自然过程。骨髓中有单个核细胞(MNC)，其中含有多潜能干细胞和其他促进血管生成的细胞成分。动物研究表明，单核细胞可以改善包括中风、心肌梗死和头部创伤在内的各种疾病的预后。在德克萨斯大学休斯顿分校，两项临床研究目前正在评估跨国公司在儿童头部创伤和充血性心力衰竭中的安全性。我们在SPOTRIAS计划拨款中提出了一项IIa期安全性研究；然而，评价者指出，仍然需要关键的动物研究来确定重要的疗效指标，包括剂量、中风后细胞给药的最佳时间和最佳给药途径。我们的初步研究表明，与赋形剂治疗的对照动物相比，动脉或静脉注射MNC(1000万)显著减少移植后1周内的神经功能缺陷，并在中风后2个月持续受益。单核细胞可以从患者自己的骨髓中获得，因此是一种有吸引力的自体移植治疗方法。因此，这项建议旨在解决发展自体骨髓单个核细胞(MNC)作为治疗缺血性中风的新疗法的关键翻译步骤。目的1明确MNCs在大脑中动脉远端可逆性闭塞模型中的剂量效应、治疗时间窗和最佳给药途径。我们已经开发了一种啮齿动物模型，可以在中风后采集骨髓，并允许单核细胞重新输注自体细胞。在目标2中，使用目标1中定义的最佳条件，我们将确定MNC在其他对中风具有临床重要性的环境中的疗效：老龄动物、导致皮质和皮质下梗塞的大脑中动脉近端闭塞，以及永久性大脑中动脉闭塞。在目标3中，我们将在栓塞性卒中模型中确定组织纤溶酶原激活剂治疗后单核细胞的安全性。这些目标将提供关键信息，用于在德克萨斯大学休斯顿分校设计一项针对缺血性中风患者的MNC的IIa期安全性研究，那里已经有广泛的基础设施来进行细胞疗法的临床安全性试验。 公共卫生相关性： 中风是成人残疾的主要原因，但对这种毁灭性的疾病几乎没有有效的治疗方法。细胞疗法是促进中风康复的一种很有前途的新方法。这项申请提出了在临床相关的中风动物模型中测试骨髓单个核细胞的关键实验。这些拟议实验的数据对于设计我们在中风患者中使用这些细胞进行的第一项临床安全性研究至关重要。

DESCRIPTION (provided by applicant): Cell therapy has emerged as a novel approach to enhance recovery from ischemic stroke. Animal stroke studies support the safety and efficacy of various types of cells derived from different tissues. Bone marrow cells may participate in natural processes of brain repair after neurological injury. Within the bone marrow reside mononuclear cells (MNCs) which contain multipotential stem cells and other cellular components that promote angiogenesis. Animal studies suggest that MNCs may improve outcome in various disorders including stroke, myocardial infarction, and head trauma. At UT-Houston, two clinical studies are currently assessing the safety of MNCs in pediatric head trauma and congestive heart failure. We proposed a phase IIa safety study in our SPOTRIAS program grant; however, the reviewers indicated that pivotal animal studies are still needed to determine important efficacy measures including dosing, optimal time after stroke for cellular administration, and best route of delivery. Our preliminary studies suggest that intra- arterial or intravenous administration of MNCs (10 million) to animals with ischemic stroke significantly reduces neurological deficits within 1 week after transplantation and the benefit is sustained 2 months after stroke, compared with vehicle-treated control animals. MNCs can be derived from a patient's own marrow and therefore represent an attractive therapeutic approach for autologous transplantation. This proposal therefore seeks to address key translational steps for the development of autologous bone marrow mononuclear cells (MNCs) as a novel therapy for ischemic stroke. Aim 1 will define a dose response, therapeutic time window, and optimal route of delivery of MNCs in the rodent model of reversible distal MCA occlusion causing cortical infarction and reperfusion injury. We have developed a rodent model that permits bone marrow harvest after stroke and MNC re-infusion of autologous cells. In Aim 2, using optimal conditions defined in Aim 1, we will determine efficacy of MNCs in other settings clinically important to stroke: aged animals, proximal MCA occlusion causing cortical and subcortical infarction, and permanent MCA occlusion. In Aim 3, we will determine the safety of MNCs following treatment with tissue plasminogen activator in an embolic stroke model. These aims will provide critical information that would be used to design a phase IIa safety study of MNCs in ischemic stroke patients at UT-Houston where there is already an extensive infrastructure to conduct clinical safety trials on cellular therapies. PUBLIC HEALTH RELEVANCE: Stroke is the leading cause of adult disability but there are few effective treatments for this devastating condition. Cell therapy is a promising new approach to enhance recovery from stroke. This application proposes critical experiments to test bone marrow mononuclear cells in clinically relevant animal models of stroke. The data from these proposed experiments are essential to design our first clinical safety study using these cells in stroke patients.