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（由申请人提供）：多发性硬化症（MS）是一种慢性且很大程度上不可预测的中枢神经系统（CNS）疾病，其特征是针对包裹 CNS 神经元的髓鞘的自身免疫活性，导致髓鞘细胞死亡，称为病变部位内的少突胶质细胞脱髓鞘或髓鞘降解是目前批准的多发性硬化症治疗方法的主要原因。旨在抑制免疫反应，但没有解决促进髓鞘再生的需要，这是在多发性硬化症病变形成后恢复功能缺陷所需的基本步骤，开发促进髓鞘再生并防止导致神经细胞死亡的不可逆转后果的治疗方法。中枢神经系统含有少突胶质细胞前体细胞 (OPC)，它们有可能分化成成熟的少突胶质细胞，从而能够进行髓鞘再生。然而，MS 损伤后残留的髓鞘碎片会抑制 OPC 分化为成熟的少突胶质细胞，这一过程需要激活小 GTP 酶 Rho，从而导致功能性成熟少突胶质细胞的缺乏和随后的髓鞘再生。加剧和持续功能缺陷，这是 MS 的标志。我们之前已经证明，低密度脂蛋白受体相关蛋白 1。 (LRP1) 是中枢神经系统中髓磷脂碎片的一种新型受体，我们还在多种细胞类型和体内模型中证明，RAP 显着减弱 RhoA 的激活。最近的研究表明，OPC 中 LRP1 的基因缺失可促进体内髓鞘再生。，在 MS 啮齿动物模型中，表明 LRP1 是髓磷脂介导的 OPC 分化抑制的新型促进剂 LRP1 缺失能够增强髓磷脂生成的 OPC 分化。结合已记录的 LRP1 拮抗剂 RAP 减弱 RhoA 激活的能力，表明 RAP 是一种新颖且令人兴奋的增强 MS 病变后髓鞘再生的治疗候选药物，因此，RAP 是通过临床前验证的重要候选药物。 -作为一种高价值潜在疗法的概念测试，用于在多发性硬化症发作后恢复髓鞘形成和神经功能。