NOVO-118 as a therapeutic to promote remyelination in in vivo models of MS

NOVO-118 作为促进多发性硬化症体内模型髓鞘再生的治疗剂

• 批准号: 10011900
• 负责人: Alban P Gaultier
• 金额: $ 35.41万
• 依托单位: NOVORON BIOSCIENCE, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10011900
• 关键词: Address; Animals; Area; Attenuated; Autoimmune Process; Axon; Biological Assay; Brain; Cell Culture Techniques; Cell Differentiation process; Cell Maturation; Cells; Cessation of life; Characteristics; Chemicals; Clinical; Confounding Factors (Epidemiology); Cuprizone; Data; Demyelinations; Development; Disease; Disease Progression; Dose; Experimental Autoimmune Encephalomyelitis; Frequencies; Future; Genetic; Goals; Histologic; Human; Immune; Immune response; Immune system; In Vitro; LDL-Receptor Related Protein 1; Lead; Lesion; Lipoprotein Receptor; Mediating; Mediator of activation protein; Modeling; Molecular Chaperones; Multiple Sclerosis; Multiple Sclerosis Lesions; Myelin; Myelin Proteins; Natural regeneration; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neuronal Dysfunction; Neurons; Oligodendroglia; Pharmaceutical Preparations; Phase; Physiological; Population; Production; Proteins; Protocols documentation; Quality Control; Severities; Severity of illness; Signaling Molecule; Site; Symptoms; Technology; Temperature; Therapeutic; Therapeutic Intervention; Time; Tissues; Toxic effect; Toxicology; Tumor-infiltrating immune cells; Validation; Work; disability; drug candidate; healing; in vivo; in vivo Model; myelination; novel lead compound; novel strategies; oligodendrocyte precursor; oligodendrocyte progenitor; pharmacokinetics and pharmacodynamics; precursor cell; prevent; programs; receptor; recruit; remyelination; repaired; response; screening; stem cells; therapeutic development

7. Project Summary Multiple sclerosis (MS) is a neurodegenerative disease in which myelin of the central nervous system (CNS) is destroyed by a self-reactive immune response. This demyelination is accompanied by the death of the myelinating cells themselves, the oligodendrocytes. Repeated bouts of demyelination leave the denuded CNS neurons vulnerable to degradation and is the major cause of neuronal dysfunction and neurodegeneration in MS. Current approved therapies for MS are aimed only at lessening the frequency of the auto-immune attack and do not address the need for remyelination. Without induction of remyelination to heal previous lesions, the course of disease can only be slowed but not reversed. The CNS contains a large population of oligodendrocyte precursor cells (OPC) that have the potential to differentiate into mature oligodendrocytes and remyelinate denuded axons. Although OPCs are efficiently recruited into MS lesions, OPC differentiation into mature oligodendrocytes, and subsequent remyelination, is inhibited in MS. Novoron has discovered that the LRP1 receptor is a key signaling molecule that prevents OPC differentiation. By abrogating LRP1 function using either genetic deletion or antagonism, we can increase OPC differentiation and restore the remyelinating capacity of the brain. The goal of this proposal is to transition from our preliminary data demonstrating our novel approach to remyelination to developing this technology into a viable human drug. By the end of this Phase 1 application, Novoron will possess the following: 1) a lead drug candidate with an in vivo dose-response profile, 2) disease efficacy data in the cuprizone chemical demyelinating model, and 3) disease efficacy data in the autoimmune- mediated EAE MS model. These data will demonstrate the feasibility of our approach to healing MS leasions and preapre Novoron for an efficient comercialization-focused Phase 2 application.

7.项目摘要 多发性硬化症（MS）是一种神经退行性疾病，其中中枢神经系统（CNS）的髓鞘被破坏。 被自身免疫反应所摧毁这种脱髓鞘是伴随着死亡的， 髓鞘形成细胞，即少突胶质细胞反复发作的脱髓鞘使裸露的中枢神经系统 神经元容易退化，是神经元功能障碍和神经变性的主要原因， 女士目前批准的MS疗法仅旨在减少自身免疫攻击的频率 并且不能解决髓鞘再生的需要。如果不诱导髓鞘再生来治愈先前的损伤， 病程只能延缓而不能逆转。 CNS含有大量的少突胶质细胞前体细胞（OPC），其具有以下潜能： 分化成成熟的少突胶质细胞并使脱髓鞘的轴突再生。虽然OPCs的效率 招募到MS病变，OPC分化成成熟的少突胶质细胞，随后髓鞘再生， Novoron发现LRP 1受体是阻止OPC的关键信号分子， 分化通过使用基因缺失或拮抗作用废除LRP 1功能，我们可以增加OPC 分化和恢复脑的髓鞘再生能力。 该提案的目标是从我们的初步数据过渡到证明我们的新方法， 髓鞘再生有助于将这项技术开发成一种可行的人类药物。在第一阶段应用结束时， Novoron将具有以下特点：1）具有体内剂量反应特征的先导候选药物，2）疾病 在铜腙化学脱髓鞘模型中的疗效数据，和3）在自身免疫性脱髓鞘模型中的疾病疗效数据。 介导的EAE MS模型。这些数据将证明我们的方法治愈MS损伤的可行性 并为Novoron进行有效的商业化第二阶段应用做好准备。