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: 9144462
• 负责人: Alban P Gaultier
• 金额: $ 32.07万
• 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/9144462
• 关键词: Address; Area; Attention; Attenuated; Autoimmune Process; Axon; Biological Sciences; 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; Health; 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; 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; multiple sclerosis patient; multiple sclerosis treatment; myelination; neuron loss; novel; novel therapeutics; oligodendrocyte precursor; pre-clinical; precursor cell; prevent; 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）是一种慢性且在很大程度上不可预测的中枢神经系统（CNS）疾病，其特征在于针对包裹CNS神经元的髓鞘的自身免疫活性，其导致病变部位内的髓鞘形成细胞（称为少突胶质细胞）死亡。由此产生的脱髓鞘或髓鞘的降解是由这种疾病引起的残疾和死亡的主要原因。目前批准的MS疗法旨在抑制免疫应答，但没有解决促进髓鞘再生的需要，这是MS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预防导致神经元细胞死亡的不可逆后果的疗法对于改善MS患者的生活质量和生存至关重要。CNS含有少突胶质细胞前体细胞（OPC），其具有分化成成熟少突胶质细胞的潜力，所述成熟少突胶质细胞然后能够在MS攻击后使裸露的轴突再髓鞘化。然而，髓鞘碎片滞留在MS病变部位抑制OPC分化为成熟的少突胶质细胞通过一个过程，需要激活的小-GTdR Rho。缺乏功能，成熟的少突胶质细胞，和随后的髓鞘再生，加剧和延续功能缺陷，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（LRP 1）是一种新的受体髓鞘碎片在中枢神经系统。我们还在多种细胞类型和体内模型中显示RAP显著减弱RhoA的激活。最近的研究表明，在MS的啮齿动物模型中，OPC中LRP 1的遗传缺失促进体内髓鞘再生，表明LRP 1是髓鞘介导的OPC抑制分化的新促进剂。LRP 1缺失增强髓鞘产生的OPC分化的能力与LRP 1拮抗剂RAP减弱RhoA激活的记录能力相结合，表明RAP是一种新的和令人兴奋的治疗候选物，用于增强MS损伤后的髓鞘再生。因此，RAP是通过临床前概念验证测试的重要候选药物，作为MS发作后恢复髓鞘形成和神经元功能的高价值潜在治疗药物。