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:
  • 金额:
    $ 41.48万
  • 依托单位:
  • 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

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.
项目概要/摘要 Abilita Bio 是一家创新驱动的生物技术公司,正在为这一发现寻求 SBIR 第一阶段资金 靶向孤儿 G 蛋白偶联受体 GPR17 和 GPR37 的新型治疗性纳米抗体 解决阿尔茨海默病的神经病理学问题。超过500万美国人患有此病 使人衰弱的疾病,导致记忆丧失和认知功能逐渐受损。 尽管有大量证据支持 β 淀粉样蛋白和 tau 蛋白在阿尔茨海默病中的作用 病因病理学、β淀粉样蛋白靶向临床努力几乎没有产生认知改善的证据 或功能性结果,强调对新靶点和治疗策略的需求未得到满足。 最近的影像学研究表明,白质结构变化和底层髓磷脂 异常是阿尔茨海默病的重要组成部分,可能先于明显的淀粉样蛋白和 tau 蛋白出现 病理学。由于白质变化和髓磷脂缺失与临床进展有关 阿尔茨海默病,神经胶质细胞负责髓鞘质、少突胶质细胞的产生和修复, 可能会受到严重影响。因此,促进少突胶质细胞成熟和髓鞘再生的药物可能 代表了阿尔茨海默病和其他神经退行性疾病的有前景的新疗法。近日,有 研究发现,两个孤儿 G 蛋白偶联受体 GPR17 和 GPR37 具有负调节作用 少突胶质细胞在成熟为髓鞘细胞时发育,最终影响其能力 修复受损的轴突。 GPR17 和 GPR37 信号传导的选择性拮抗剂可能会解除阻断 少突胶质细胞检查点促进其分化和髓鞘再生活性,这呈现出 修复阿尔茨海默病造成的病理损伤的机会。 尽管 GPR17 和 GPR37 具有潜力,但尚无特定的药物制剂可用于 用于验证阿尔茨海默病的靶标,或作为治疗线索,我们将在 拟议的研究。 GPR17 和 GPR37 由于其性能较差而极难药物化。 明确的结合口袋、功能折叠差和高组成活性,这是孤儿药的典型特征 受体。我们将通过使用一种新颖的方法来满足选择性靶标调节剂的需求,其中我们 将使用我们创新的基于定向进化的蛋白质稳定技术来优化 GPR17 和 GPR37 用于骆驼免疫和噬菌体库筛选以发现骆驼单链 抗体(纳米抗体)。纳米抗体具有独特的特性,能够识别受体结合 对于 G 蛋白偶联受体的功能调节至关重要的口袋和结构元件 已被成功的临床开发所验证。我们计划发现竞争性和对抗性 纳米抗体将进行药理学表征并测试其刺激能力 少突胶质细胞成熟和髓鞘形成活性。经验证纳米抗体具有效力和选择性 这些测定中的结果将在未来的阶段在阿尔茨海默病模型中进行体内验证 II SBIR 努力,以临床开发为目标。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Mauro Mileni其他文献

Mauro Mileni的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Mauro Mileni', 18)}}的其他基金

Novel Anti-CCR8 VHH for the Treatment of NSCLC
用于治疗 NSCLC 的新型抗 CCR8 VHH
  • 批准号:
    10760140
  • 财政年份:
    2023
  • 资助金额:
    $ 41.48万
  • 项目类别:
Discovery of Novel Blood-Brain Barrier Targeting Antibodies for the Treatment of Alzheimer's Disease
发现用于治疗阿尔茨海默病的新型血脑屏障靶向抗体
  • 批准号:
    10254514
  • 财政年份:
    2021
  • 资助金额:
    $ 41.48万
  • 项目类别:
Discovery of therapeutic antibodies targeting breast cancer metastasis using Enabled G-Protein-Coupled Receptors
使用启用的 G 蛋白偶联受体发现针对乳腺癌转移的治疗抗体
  • 批准号:
    9256138
  • 财政年份:
    2016
  • 资助金额:
    $ 41.48万
  • 项目类别:

相似海外基金

RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
  • 批准号:
    2327346
  • 财政年份:
    2024
  • 资助金额:
    $ 41.48万
  • 项目类别:
    Standard Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
  • 批准号:
    2312555
  • 财政年份:
    2024
  • 资助金额:
    $ 41.48万
  • 项目类别:
    Standard Grant
How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
  • 批准号:
    BB/Z514391/1
  • 财政年份:
    2024
  • 资助金额:
    $ 41.48万
  • 项目类别:
    Training Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
  • 批准号:
    ES/Z502595/1
  • 财政年份:
    2024
  • 资助金额:
    $ 41.48万
  • 项目类别:
    Fellowship
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
  • 批准号:
    ES/Z000149/1
  • 财政年份:
    2024
  • 资助金额:
    $ 41.48万
  • 项目类别:
    Research Grant
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
  • 批准号:
    23K24936
  • 财政年份:
    2024
  • 资助金额:
    $ 41.48万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
  • 批准号:
    2901648
  • 财政年份:
    2024
  • 资助金额:
    $ 41.48万
  • 项目类别:
    Studentship
ERI: Developing a Trust-supporting Design Framework with Affect for Human-AI Collaboration
ERI:开发一个支持信任的设计框架,影响人类与人工智能的协作
  • 批准号:
    2301846
  • 财政年份:
    2023
  • 资助金额:
    $ 41.48万
  • 项目类别:
    Standard Grant
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
  • 批准号:
    488039
  • 财政年份:
    2023
  • 资助金额:
    $ 41.48万
  • 项目类别:
    Operating Grants
How motor impairments due to neurodegenerative diseases affect masticatory movements
神经退行性疾病引起的运动障碍如何影响咀嚼运动
  • 批准号:
    23K16076
  • 财政年份:
    2023
  • 资助金额:
    $ 41.48万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了