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

• 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
• 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

 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，导致病变部位内的髓鞘细胞（称为少突胶质细胞）死亡。由此产生的脱髓鞘或髓鞘退化是导致这种疾病导致残疾和死亡的主要原因。目前批准的多发性硬化症疗法旨在抑制免疫反应，但没有解决促进髓鞘再生的需要，而髓鞘再生是多发性硬化症病变形成后恢复功能缺陷所需的基本步骤。开发促进髓鞘再生和防止导致神经细胞死亡的不可逆转后果的疗法对于改善多发性硬化症患者的生活质量和生存至关重要。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，从而能够在多发性硬化症攻击后对裸露的轴突进行髓鞘再生。然而，残留在多发性硬化症病变部位的髓磷脂碎片通过需要激活小 GTP 酶 Rho 的过程抑制 OPC 分化为成熟的少突胶质细胞。功能性成熟少突胶质细胞的缺乏以及随后的髓鞘再生会加剧并延续功能缺陷，而功能缺陷是多发性硬化症的标志。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，在 MS 啮齿动物模型中，OPC 中 LRP1 的基因缺失可促进体内髓鞘再生，表明 LRP1 是髓磷脂介导的 OPC 分化抑制的新型促进剂。 LRP1 缺失增强髓磷脂生成的 OPC 分化的能力，结合已记录的 LRP1 拮抗剂 RAP 减弱 RhoA 激活的能力，表明 RAP 是一种新的、令人兴奋的治疗 MS 损伤后增强髓鞘再生的候选药物。因此，RAP 是通过临床前概念验证测试作为一种高价值潜在疗法的重要候选药物，用于在多发性硬化症发作后恢复髓鞘形成和神经元功能。