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: 9053058
• 负责人: Shanta Dhar
• 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/9053058
• 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; Endothelial Cells; Environment; Family; Family suidae; Glycolates; Health; Human; Image; 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; Outcome; 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 tissue; cytokine; cytotoxic; disability; functional outcomes; improved; in vitro Model; in vivo; induced pluripotent stem cell; interest; kinematics; mitochondrial membrane; multidisciplinary; nanomedicine; nanoparticle; nerve stem cell; programs; public health relevance; regenerative; regenerative therapy; screening; socioeconomics; stem cell therapy; 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（由申请人提供）：中风是残疾的主要原因，也是美国成年人死亡的第四大原因。纤溶酶原激活剂仍然是唯一的食品和药物管理局（FDA）批准的中风治疗药物。然而，这种治疗在有效性、安全性和有效性窗口方面具有显著的局限性。缺乏任何有效的恢复药理学方法表明迫切需要基于干细胞的治疗。一类新的自体神经干细胞（NSCs）被称为诱导多能干细胞衍生的NSCs（iNSCs），其具有分化为神经元、星形胶质细胞和胶质细胞的能力。 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群体。然而，这些细胞由于其在中风后具有高水平活性氧（ROS）和炎性细胞因子的细胞毒性环境下的存活问题而显示出显著的功效变异性。这表明，用适当递送至靶组织的抗氧化剂和抗炎剂对受损脑进行预处理将显著改善移植物的存活率，并最终改善组织和功能结果。我们最近开发了一种高度亲脂的可生物降解的纳米颗粒（NP）递送平台，其具有穿过血脑屏障（BBB）并在炎症扩散的脑的白色物质中的富含ROS和抗炎剂的线粒体基质内递送抗氧化剂的能力。 有了这一成功，我们假设，在大型动物模型（如具有与人类相似大脑的猪）中，基于联合NP递送的神经保护素-干细胞疗法的治疗选择的开发可能是非常有益的。为了构建该NP平台并证明其潜力，我们定义了以下具体目的：（1）构建并体外优化BBB穿透靶向的可生物降解的含有线粒体作用的抗氧化剂和抗炎剂的NP;（2）安全性、毒性、在正常仔猪中的分布以及在猪大脑中动脉闭塞（MCAO）缺血损伤模型中的治疗功效;（3）在猪MCAO中风模型中的组合治疗性NP-干细胞疗法。 本研究将为脑卒中后神经保护素-干细胞联合治疗提供一个潜在的纳米医学平台。靶向的纳米颗粒的组成简单，并且由良好表征的可生物降解的靶向部分附加的聚合物构建，这将非常有利于临床翻译。