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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：
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
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/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

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.