RAP as a novel therapeutic to promote remyelination after MS demyelinating event

RAP 作为促进 MS 脱髓鞘事件后髓鞘再生的新型疗法

基本信息

批准号：
8981311
负责人：
Alban P Gaultier
金额：
$ 35.31万
依托单位：
NOVORON BIOSCIENCE, INC.
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：
2015-09-15 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8981311
关键词：
Address Area Attention Attenuated Autoimmune Process Axon Blood - brain barrier anatomy Brain Cause of Death Cell Differentiation process Cell Surface Receptors Cells Central Nervous System Diseases Cessation of life Chronic Demyelinations Disease Encapsulated Event Experimental Autoimmune Encephalomyelitis Genetic Goals Immune response In Vitro Infusion procedures Intravenous LDL-Receptor Related Protein 1 LDL-Receptor Related Proteins Lesion Lipoprotein Receptor Lysophosphatidylcholines Mediating Modeling Monomeric GTP-Binding Proteins Multiple Sclerosis Multiple Sclerosis Lesions Myelin Myelin Proteins Myelin Sheath Nerve Degeneration Neuraxis Neurodegenerative Disorders Neuronal Dysfunction Neurons Oligodendroglia Patients Peripheral Phagocytosis Population Prevention Process Production Proteins Protocols documentation Quality of life Recruitment Activity Research Rho-associated kinase Rodent Model Route Signal Transduction Site Spinal Cord Stem cells Testing Therapeutic Transferase Work axon regeneration cell type disability improved in vivo in vivo Model inhibitor/antagonist interest intravenous administration myelination neuron loss novel novel therapeutics oligodendrocyte precursor pre-clinical precursor cell prevent public health relevance receptor remyelination response rho therapeutic development therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is a chronic and largely unpredictable disease of the central nervous system (CNS) characterized by autoimmune activity against the myelin sheath encapsulating CNS neurons, which results in death of the myelinating cells, known as oligodendrocytes, within the lesion site. Resultant demyelination, or degradation of the myelin sheath, is the major contributor to the disability and death caused by this disease. Currently approved therapies for MS are aimed at inhibition of the immune response, but do not address the need to promote remyelination, which is the fundamental step needed to restore functional deficits after MS lesion formation. Development of therapeutics that promote remyelination and prevent irreversible consequences leading to neuronal cell death is paramount to improving the quality of life and survival of MS patients. The CNS contains oligodendrocyte precursor cells (OPCs) that have the potential to differentiate into mature oligodendrocytes, which would then be capable of remyelination of denuded axons after an MS attack. However, myelin debris lingering at MS lesion sites inhibits the differentiation of OPCs into mature oligodendrocytes through a process that requires that activation of the small-GTPase Rho. The lack of functional, mature oligodendrocytes, and subsequent remyelination, exacerbates and perpetuates functional deficits that are the hallmark of MS. We have previously demonstrated that the low-density lipoprotein receptor-related protein-1 (LRP1) is a novel receptor for myelin debris in the CNS. We have also shown in multiple cell types and in vivo models that RAP significantly attenuates activation of RhoA. More recent studies have demonstrated that genetic deletion of LRP1 in OPCs promotes remyelination in vivo, in rodent models of MS, indicating that LRP1 is a novel facilitator of myelin-mediated OPC suppression of differentiation. The ability of LRP1 deletion to enhance OPC differentiation of myelin production combined with the documented capacity of the LRP1 antagonist RAP to attenuate activation of RhoA indicate that RAP is a novel and exciting therapeutic candidate for enhancement of remyelination after MS lesion. As such, RAP is an important candidate to bring through pre-clinical proof-of-concept testing as a high-value potential therapeutic for restoring myelination and neuronal function after MS attack.

描述（由应用程序提供）：多发性硬化症（MS）是一种慢性且在很大程度上是不可预测的中枢神经系统（CNS）的疾病，其特征是针对包含CNS神经元的髓磷脂鞘的自身免疫性活性，导致骨髓细胞死亡，被称为寡头细胞，在Lesion位置内。由此导致髓鞘鞘的脱髓鞘或降解是导致这种疾病造成的残疾和死亡的主要因素。当前批准的MS疗法旨在抑制免疫响应，但并未满足促进延期性的需求，这是恢复MS病变形成后功能定义所需的基本步骤。开发促进透明度并防止导致神经元细胞死亡的不可逆后果的治疗剂的发展对于改善MS患者的生活质量和存活至关重要。中枢神经系统包含少突胶质前体细胞（OPC），这些细胞（OPC）有可能区分成熟的少突胶质细胞，然后在MS攻击后能够对裸轴突进行再效率。然而，MS病变位点徘徊的髓磷脂碎片通过一个过程，抑制OPC通过一个需要激活小型GTPase Rho的过程，将OPC的分化为成熟的少突胶质细胞。缺乏功能性，成熟的少突胶质细胞以及随后的再生，加剧和永久性的功能缺陷，这是MS的标志。我们以前已经证明，低密度脂蛋白受体相关蛋白-1（LRP1）是CNS中髓磷脂碎屑的新型受体。我们还显示了多种细胞类型和体内模型，这些模型大大减弱了RhoA的激活。最近的研究表明，在MS的啮齿动物模型中，OPC中LRP1的遗传缺失促进了体内的rembleelination，这表明LRP1是髓磷脂介导的OPC抑制分化的新型促进因子。 LRP1删除增强髓磷脂产生的OPC分化的能力以及LRP1拮抗剂RAP的证明能力减弱了RhoA的激活，这表明RAP是一种新颖而令人兴奋的治疗候选者，可增强MS病变后的Remyelination。因此，RAP是将临床前概念验证测试作为MS攻击后恢复髓鞘恢复和神经元功能的高价值治疗的重要候选者。