Discovery of therapeutic nanobodies targeting the G protein-coupled receptors in the brain for the treatment of Alzheimer Disease

发现针对大脑中 G 蛋白偶联受体的治疗性纳米抗体可用于治疗阿尔茨海默病

基本信息

批准号：
9910106
负责人：
Mauro Mileni
金额：
$ 41.48万
依托单位：
ABILITA BIO, 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：
2019-09-01 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9910106
关键词：
Address Affect Agonist Alzheimer&apos s Disease Alzheimer&apos s disease model American Amyloid Amyloid beta-Protein Antibodies Antigen Receptors Antigens Axon Bacteriophages Binding Biological Assay Biotechnology Brain Brain Diseases Cells Clinical Cognitive Demyelinations Development Directed Molecular Evolution Disease Drug Targeting Elements Evolution Exhibits Failure Funding Future Future Generations G-Protein-Coupled Receptors G-substrate GPR17 gene Immunization Impaired cognition Libraries Llama Membrane Proteins Memory Loss Molecular Conformation Morphology Mutation Myelin Neurodegenerative Disorders Neuroglia Oligodendroglia Orphan Pathogenicity Pathologic Pathology Patients Phage Display Pharmaceutical Preparations Pharmacology Phase Phenotype Process Production Property Proteins Reporting Research Risk Role Senile Plaques Signal Transduction Small Business Innovation Research Grant Structural defect Structure Technology Testing Therapeutic Therapeutic antibodies United States Validation Variant aging population axon injury base clinical development cognitive function design functional outcomes gray matter imaging study improved in vitro Model in vivo innovation myelination nanobodies neuroimaging neuropathology novel novel strategies novel therapeutics oligodendrocyte progenitor preclinical development receptor receptor binding remyelination repaired screening targeted treatment tau Proteins tau aggregation therapeutic development tool white matter white matter change

项目摘要

Project Summary/Abstract Abilita Bio, an innovation-driven biotechnology company, is seeking SBIR Phase I funding for the discovery of novel therapeutic nanobodies targeting the orphan G protein-coupled receptors GPR17 and GPR37, to address the neuropathology of Alzheimer’s disease. More than 5 million Americans suffer from this debilitating disease, which causes memory loss and the progressive impairment of cognitive functions. Despite an abundance of evidence supporting the role of amyloid-β and tau in Alzheimer’s disease etiopathology, amyloid-β targeted clinical efforts have generated little evidence of improvement in cognitive or functional outcomes, which emphasizes the unmet need for novel targets and therapeutic strategies. Recent imaging studies have demonstrated that white matter structural changes and underlying myelin abnormalities are significant components of Alzheimer’s disease and may precede overt amyloid and tau pathologies. Due to the association of white matter changes and myelin loss with the clinical progression of Alzheimer’s disease, the glial cells responsible for the production and repair of myelin, oligodendrocytes, may be critically affected. Therefore, drugs that promote oligodendrocyte maturation and remyelination may represent promising new treatments for Alzheimer’s and other neurodegenerative diseases. Recently, it has been found that two orphan G protein-coupled receptors, GPR17 and GPR37, act to negatively regulate oligodendrocyte development as they mature to myelinating cells, which and ultimately affects their capacity to repair damaged axons. Selective antagonists of GPR17 and GPR37 signaling may unblock oligodendrocyte checkpoints to promote their differentiation and remyelinating activity, which presents an opportunity to repair the pathological damage caused by Alzheimer’s. Despite the potential of GPR17 and GPR37, no specific pharmacological agents are available that can be used to validate the targets in Alzheimer’s disease, or serve as therapeutic leads, which we will address in the proposed research. GPR17 and GPR37 have been exceedingly difficult to drug due to their poorly defined binding pockets, poor functional folding and high constitutively activity, which is typical for orphan receptors. We will address the need for selective target modulators by using a novel approach, where we will use our innovative directed evolution-based protein stabilization technology to optimize GPR17 and GPR37 for use in llama immunization and phage library screening for the discovery of camelid single chain antibodies (nanobodies). Nanobodies have unique properties that enable the recognition of receptor binding pockets and structural elements critical for the functional modulation of G protein-coupled receptors and have been validated by successful clinical development. We plan to discover both agonistic and antagonistic nanobodies that will be pharmacologically characterized and tested for their ability to stimulate oligodendrocyte maturation and myelination activity. Nanobodies verified to exhibit potency and selectivity in these assays will be taken forward to in vivo validation in Alzheimer’s Disease models in a future Phase II SBIR effort, with the aim of clinical development.

项目摘要/摘要创新驱动的生物技术公司Abilita Bio正在寻求SBIR I阶段资金进行发现针对孤儿G蛋白偶联受体GPR17和GPR37的新型热纳米体的解决阿尔茨海默氏病的神经病理学。超过500万美国人遭受这一苦难使人衰弱的疾病，这会导致记忆力丧失和认知功能的进行性损害。尽管有大量证据支持淀粉样蛋白β和tau在阿尔茨海默氏病中的作用病理学，淀粉样β靶向临床努力几乎没有得到认知改善的证据或功能结果，强调对新目标和治疗策略的未满足的需求。最近的成像研究表明，白质结构发生变化和髓磷脂的基础异常是阿尔茨海默氏病的重要组成部分，可以在明显的淀粉样蛋白和tau之前病理。由于白质变化和髓磷脂损失与临床进展的关联阿尔茨海默氏病，负责髓磷脂的生产和修复的神经胶质细胞，少突胶质细胞，可能受到严重影响。因此，可以促进少突胶质细胞成熟和恢复原状的药物可能代表对阿尔茨海默氏症和其他神经退行性疾病的新疗法。最近，它有发现两个孤儿G蛋白偶联受体GPR17和GPR37作用着负调节少突胶质细胞成熟到髓鞘细胞，并最终影响其能力修复受损的轴突。 GPR17和GPR37信号的选择性拮抗剂可能会取消阻碍少突胶质细胞检查点以促进其分化和延期活动，这表明修复阿尔茨海默氏症造成的病理损害的机会。尽管GPR17和GPR37有可能用于验证阿尔茨海默氏病的目标，或用作治疗铅，我们将在拟议的研究。 GPR17和GPR37由于其差而难以吸毒定义的结合口袋，功能折叠不良和高度组成性活动，这对于孤儿来说是典型的接收者。我们将通过使用新颖的方法来满足选择性目标调节器的需求将使用我们创新的基于进化的蛋白质稳定技术来优化GPR17和 GPR37用于骆驼免疫化和噬菌体库筛查，以发现骆驼单链抗体（纳米生物）。纳米型具有独特的特性，可以识别受体结合口袋和结构元素对于G蛋白偶联受体的功能调节至关重要已通过成功的临床开发来验证。我们计划发现激动和拮抗将在药理学表征和测试其刺激的能力的纳米生物上少突胶质细胞的成熟和髓鞘化活性。纳米型验证为展示效力和选择性在这些测定中，将在未来的阶段进行体内验证 II SBIR努力，目的是临床开发。