Increased Therapeutic Potential of Migrating Neural Stem Cells & ASC101 Treatment

迁移神经干细胞的治疗潜力增加

• 批准号: 8455805
• 负责人: LEONARD P MILLER
• 金额: $ 33.54万
• 依托单位: TARGAZYME, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8455805
• 关键词: Affect; Americas; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Applications Grants; Astrocytes; Axon; Biological Assay; Blood - brain barrier anatomy; Brain; Cell surface; Cells; Cicatrix; Clinical; Clinical Trials; Cyclic GMP; Data; Demyelinating Diseases; Disease; Enzymes; Experimental Autoimmune Encephalomyelitis; Florida; Fluorescence; Funding; Glial Fibrillary Acidic Protein; Goals; Grant; Guanosine Diphosphate Fucose; High Pressure Liquid Chromatography; Homing; Impaired cognition; In Vitro; Individual; Inflammation; Inflammatory; Injection of therapeutic agent; Intravenous; Investigational New Drug Application; Label; Lesion; Ligands; Link; Manufacturer Name; Mediating; Membrane Glycoproteins; Modeling; Modification; Monitor; Multiple Sclerosis; Multiple Sclerosis Lesions; Mus; Myelin; Myelin Basic Proteins; Neuroglia; Neurons; Oligodendroglia; Oregon; Outcome; PDGFRB gene; Pathology; Patients; Phase; Physiological; Platelet-Derived Growth Factor alpha Receptor; Positioning Attribute; Primates; Procedures; Production; Reagent; Research; Safety; Schedule; Selectins; Sensory; Site; Slice; Small Business Innovation Research Grant; Spinal Cord; Staining method; Stains; Stem cells; Subfamily lentivirinae; T-Lymphocyte; Tail; Technology; Testing; Therapeutic; Tissues; Toxicology; Trypan Blue; Veins; angiogenesis; base; design; efficacy testing; enzyme substrate; functional decline; immunocytochemistry; improved; in vivo; injured; intravenous administration; migration; motor impairment; mouse model; nerve stem cell; neurofilament; nonhuman primate; novel; prevent; progenitor; public health relevance; relating to nervous system; remyelination; repaired; research study; shear stress; stem cell differentiation

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) affects 1 in 1000 individuals in the US and is characterized by progressive sensory, motor and cognitive impairments. These functional deficits are linked to inflammatory attacks on myelin, oligodendrocytes, and axons. Therapeutic strategies that promote remyelination, protect against inflammation, and protect axons have the potential to prevent and even improve functional declines in MS patients. One therapeutic approach is to use neural stem cells (NSCs), which are able to rescue endangered host neurons and glial cells by providing trophic support, detoxifying the microenvironment, mobilizing endogenous progenitors, triggering self-repair mechanisms, exerting anti-inflammatory and anti-scarring actions, and promoting angiogenesis. Each of these effects has the potential to improve outcomes in MS patients. Intravenous administration of NSCs is an alternative to direct injections into the CNS. This approach is feasible because systemically administered NSCs can circumvent the blood-brain barrier (BBB) and localize to a site of intracranial pathology. However, one limitation of this approach is that NSCs are extremely inefficient (<5% cells) at homing, even to an injured site in the brain. We have found that the molecules mediating homing in NSCs are defective, which contributes to the poor efficiency of NSC homing. Our preliminary in vitro data show that our proprietary technology, ASC-101, corrects this natural deficiency and improves interactions of NSCs under conditions of physiological shear stress. This Phase I SBIR grant submission is designed to generate a proof-of-principle that ex vivo correction of NSC homing molecules will improve their homing to MS lesions in a mouse model of MS. In Aim 1 we will complete the production of research-grade ASC-101 for use in experiments under this grant. In Aim 2, ASC- 101-treated NSCs will be intravenously injected in experimental autoimmune encephalomyelitis (EAE) mice and we will evaluate their migration to the lesions, differentiation and overall efficacy. EAE is a widely accepted and utilized animal model of MS. If successful, this project will provide the basis for further testing ASC-101 technology in additional animal models of MS using NSCs.

描述（由申请人提供）：在美国，千分之一的人患有多发性硬化症（MS），其特点是进行性感觉、运动和认知障碍。这些功能缺陷与髓磷脂、少突胶质细胞和轴突的炎症攻击有关。促进髓鞘再生、预防炎症和保护轴突的治疗策略有可能预防甚至改善多发性硬化症患者的功能衰退。一种治疗方法是使用神经干细胞（NSC），它能够通过提供营养支持、解毒微环境、动员内源性祖细胞、触发自我修复机制、发挥抗炎和抗衰老作用来拯救濒危的宿主神经元和神经胶质细胞。疤痕作用，并促进血管生成。这些效应中的每一种都有可能改善多发性硬化症患者的预后。静脉注射 NSC 是直接注射到 CNS 的替代方法。这种方法是可行的，因为全身给药的 NSC 可以绕过血脑屏障 (BBB) 并定位到颅内病理部位。然而，这种方法的一个局限性是，神经干细胞的归巢效率极低（<5% 细胞），即使归巢到大脑受伤部位也是如此。我们发现NSCs中介导归巢的分子存在缺陷，这导致NSCs归巢效率较低。我们的初步体外数据表明，我们的专有技术 ASC-101 可以纠正这种天然缺陷，并改善 NSC 在生理剪切应力条件下的相互作用。本次 I 期 SBIR 拨款申请旨在产生原理证明，即 NSC 归巢分子的离体校正将改善其在 MS 小鼠模型中对 MS 病变的归巢。在目标 1 中，我们将完成研究级 ASC-101 的生产，用于本次拨款下的实验。在目标 2 中，将经 ASC-101 处理的 NSC 静脉注射到实验性自身免疫性脑脊髓炎 (EAE) 小鼠中，我们将评估它们向病变的迁移、分化和总体疗效。 EAE是一种被广泛接受和使用的MS动物模型。如果成功，该项目将为使用 NSC 在其他 MS 动物模型中进一步测试 ASC-101 技术奠定基础。