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

基本信息

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
项目类别：
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

项目摘要

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.