Combined Nanoparticle and Neural Stem Cell Therapies in a Pig Model of Stroke

纳米颗粒和神经干细胞联合疗法在猪中风模型中的应用

• 批准号: 9147015
• 负责人: Franklin D West
• 金额: $ 47.86万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9147015
• 关键词: Adult; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Apoptosis; Aspirin; Astrocytes; Autologous; Biodistribution; Biological Assay; Blood - brain barrier anatomy; Brain; Brain Injuries; Cations; Cause of Death; Cell Therapy; Cells; Clinical; Coenzyme Q10; Communities; Devices; Diffuse; Disabled Persons; Drug Kinetics; Effectiveness; Encephalitis; Environment; Family; Family suidae; Glycolates; Health; Human; In Vitro; Individual; Inflammatory; Injury; Ischemic Stroke; Kinetics; Location; Measurement; Measures; Membrane Potentials; Middle Cerebral Artery Occlusion; Mitochondria; Mitochondrial Matrix; Modeling; Motor; Neurons; Neuroprotective Agents; Oligodendroglia; Oxidative Stress; Patients; Pharmaceutical Preparations; Plasminogen Activator; Polyethylene Glycols; Polymers; Population; Prevention; Property; Public Health; Reactive Oxygen Species; Recovery; Recovery of Function; Research; Research Personnel; Rodent Model; Safety; Stem cells; Stroke; Therapeutic; Therapeutic Studies; Tissues; Toxic effect; Translations; Transplantation; Treatment Efficacy; United States; United States Food and Drug Administration; Universities; Work; base; brain endothelial cell; brain tissue; cytokine; cytotoxic; disability; functional outcomes; histological image; improved; improved outcome; in vitro Model; in vivo; induced pluripotent stem cell; interest; kinematics; mitochondrial membrane; multidisciplinary; nanomedicine; nanoparticle; nerve stem cell; programs; regenerative; regenerative therapy; screening; socioeconomics; stem cell therapy; stroke treatment; success; therapeutic development; therapeutic evaluation; white matter

 DESCRIPTION (provided by applicant): Stroke is the leading cause of disability and the fourth leading cause of death amongst adults in the United States. Plasminogen activator remains the only food and drug administration (FDA)-approved drug for stroke treatment. However this treatment has significant limitations in efficacy, safety, and the window of effectiveness. The lack of any effective restorative pharmacological approaches indicates the urgent need of stem cell-based therapies. A new class of autologous neural stem cells (NSCs) known as induced pluripotent stem cell derived NSCs (iNSCs) with abilities to differentiate into neurons, astrocytes and oligodendrocytes and to integrate into damaged brain tissue represents an exciting regenerative therapeutic population. However, these cells show significant variability in efficacy due to their survival issues under the cytotoxic environment after stroke with high levels of reactive oxygen species (ROS) and inflammatory cytokines. This suggests that pre-treatment of the damaged brain with anti-oxidant and anti-inflammatory agents appropriately delivered to the target tissue would significantly improve survival of transplants and ultimately tissue and functional outcomes. We recently developed a highly lipophilic biodegradable nanoparticle (NP) delivery platform with ability to cross the blood brain barrier (BBB) and deliver anti-oxidant insie the mitochondrial matrix rich in ROS and anti-inflammatory agent in the white matter of the brain where inflammation is diffused. With this success, we hypothesized that development of therapeutic options based on combined NP delivered neuroprotectant-stem cell therapy after stroke in a large animal model such as pig with brains similar to human can be extremely beneficial. To construct this NP platform and to demonstrate its potential, we have defined the following Specific Aims: (1) Construction and in vitro optimization of a BBB penetrating targeted biodegradable NP containing mitochondria acting anti-oxidant and anti-inflammatory agents; (2) Safety, toxicity, distribution in normal piglet and therapeutic efficacy in a pig middle cerebral artery occlusion (MCAO) ischemic injury model; (3) Combined therapeutic NP-stem cell therapy in a pig MCAO stroke model. This study will provide a potential nanomedicine platform for combined neuroprotectant-stem cell therapy after stroke. The targeted NPs are simple in composition and constructed from a well characterized biodegradable targeting moiety appended polymer which will be extremely beneficial for clinical translation.

 描述（由适用提供）：中风是美国成年人中残疾的主要原因，也是第四大死亡原因。纤溶酶原激活剂仍然是唯一用于中风治疗的药物治疗药物（FDA）的药物。但是，这种治疗方法在有效性，安全性和有效性窗口上存在重大局限性。缺乏任何有效的恢复性药物方法表明迫切需要基于干细胞的疗法。一种新的自体神经元干细胞（NSC），称为诱导多能干细胞衍生的NSC（INSC），能力分化为神经元，星形胶质细胞 和少突胶质细胞并整合到受损的脑组织中，代表了令人兴奋的再生治疗种群。然而，这些细胞在中风后具有高水平的活性氧（ROS）和炎症细胞因子后，由于其在细胞毒性环境下的生存问题而引起的效率显着差异。 This suggests that pre-treatment of the damaged brain with anti-oxidant and anti-inflammatory agents appropriately delivered to the target tissue We recently developed a highly lipophilic biodegradable nanoparticle (NP) delivery platform with ability to cross the blood brain barrier (BBB) ​​and deliver anti-oxidant insie the mitochondrial matrix rich in ROS and anti-inflammatory agent in the white matter of the brain where感染扩散。通过这一成功，我们假设基于在大型动物模型中，基于中风后的NP递送神经保护剂 - 茎疗法的治疗选择的发展，例如与人类类似的大脑的猪可能非常有益。为了构建该NP平台并证明其潜力，我们定义了以下特定目的：（1）构建和体外优化BBB穿透性靶向的可生物降解的NP，其中含有线粒体作用抗氧化剂和抗炎剂； （2）猪中大脑动脉阻塞（MCAO）缺血性损伤模型中的安全性，毒性，正常小猪的分布和治疗效果； （3）在猪MCAO中风模型中联合治疗NP-STEM细胞疗法。这项研究将为中风后联合神经保护剂 - 茎疗法提供潜在的纳米医学平台。靶向的NP在组成方面很简单，并根据具有良好特征的可生物降解的靶向部分附加聚合物构建，这对临床翻译非常有益。