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

基本信息

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
项目类别：
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

项目摘要

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.

七、项目概要多发性硬化症（MS）是一种神经退行性疾病，其中中枢神经系统（CNS）的髓磷脂被破坏被自身反应性免疫反应破坏。这种脱髓鞘伴随着细胞的死亡髓鞘细胞本身，即少突胶质细胞。反复发作的脱髓鞘使中枢神经系统裸露神经元容易退化，是神经元功能障碍和神经变性的主要原因多发性硬化症。目前批准的多发性硬化症疗法仅旨在减少自身免疫攻击的频率并且不解决髓鞘再生的需要。如果没有诱导髓鞘再生来治愈先前的病变，病程只能减缓，不能逆转。中枢神经系统含有大量的少突胶质细胞前体细胞 (OPC)，它们有潜力分化为成熟的少突胶质细胞并对裸露的轴突进行髓鞘再生。尽管 OPC 非常有效招募到 MS 病变中，OPC 分化为成熟的少突胶质细胞，并随后进行髓鞘再生， MS 中受到抑制。 Novoron 发现 LRP1 受体是预防 OPC 的关键信号分子差异化。通过使用基因删除或拮抗消除 LRP1 功能，我们可以增加 OPC 分化并恢复大脑的髓鞘再生能力。该提案的目标是将我们展示新方法的初步数据转变为髓鞘再生，将这项技术开发成一种可行的人类药物。到第一阶段申请结束时， Novoron 将拥有以下特性：1) 具有体内剂量反应特征的主要候选药物，2) 疾病铜宗化学脱髓鞘模型中的功效数据，以及 3) 自身免疫模型中的疾病功效数据介导的EAE MS模型。这些数据将证明我们治疗多发性硬化症病变方法的可行性并为 Novoron 的高效商业化二期应用做好准备。