A novel approach to restricting the spread of neurofibrillary tau

限制神经原纤维 tau 蛋白扩散的新方法

• 批准号: 10579696
• 负责人: KENNETH Stephen KOSIK
• 金额: $ 3.68万
• 依托单位: NOVORON BIOSCIENCE, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10579696
• 关键词: Affect; Affinity; Age; Alzheimer' s Disease; Amyloid beta-Protein; Biological Sciences; Brain; Cytoskeletal Proteins; Dementia; Disease; Goals; Human; Impaired cognition; LDL-Receptor Related Protein 1; Lead; Nerve Degeneration; Neurofibrillary Tangles; Pathology; Patients; Persons; Pharmaceutical Preparations; Population; Process; Risk; Rodent; Rodent Model; Senile Plaques; Tauopathies; Technology; Testing; Therapeutic; Translating; abeta accumulation; antagonist; clinically relevant; clinically translatable; design; functional outcomes; improved; intravenous administration; novel; novel strategies; pre-clinical; receptor; subcutaneous; targeted treatment; tau Proteins; therapeutic target; therapy development; uptake

7. Project Summary Alzheimer’s disease (AD) is the most common cause of dementia and is a growing problem as populations age. More than 25 million people are affected by dementia worldwide with most suffering from AD. AD is characterized by the presence of plaques of insoluble amyloid-beta (Aβ) and tangles of hyperphosphorylated aggregates of the cytoskeletal protein, tau. Thus far, most AD treatments have targeted Aβ aggregation and plaque formation, but these therapies have largely failed to translate from preclinical rodent models to humans. Interestingly, tau pathology has been shown to correlate better with cognitive decline than Aβ, and thus restricting the spread of neurofibrillary tau has become a growing focus for development of treatments for various tauopathies, including AD. It was recently discovered that LRP1 is a master regulator of tau uptake and spread in the brain, indicating that LRP1 may be an important therapeutic target for slowing the progression of various tauopathies. Novoron Bioscience is developing novel large-molecule therapies targeting LDL receptor-related protein 1 (LRP1), a master regulator of tau uptake and spread in the brain, to slow the progression of tauopathies such as (AD) and improve functional outcomes in patients. Novoron’s lead compound, NOVO-118, is a high-affinity LRP1 antagonist that is actively taken up into the brain via both subcutaneous and intravenous administration. The purpose of this proposal is to evaluate the therapeutic potential of NOVO-118 by assessing its ability to restrict the spread of tau in the rodent brain. We will accomplish this by uncoupling proof of concept studies for effective tau restriction from assessment of translatability in terms of clinically relevant utilization. To accomplish this, we have designed this project with two primary goals: 1) generate necessary proof of concept demonstrating the ability of NOVO-118 to abrogate tau spread; and 2) de-risk the technology by demonstrating that we can deliver the drug and elicit benefit in a clinically translatable fashion.

7。项目摘要 阿尔茨海默氏病（AD）是痴呆症的最常见原因，并且随着人群的年龄而越来越多的问题。 超过2500万人受到全世界痴呆症的影响，大多数患有广告。广告是特征的 通过存在不溶性淀粉样蛋白β（Aβ）的斑块和缠结 细胞骨架蛋白，tau。大多数AD处理的远处是Aβ聚集和斑块形成， 但是这些疗法在很大程度上未能将临床前啮齿动物模型转化为人类。有趣的是，tau 病理已显示与Aβ相比，与认知下降更好地相关，因此限制了 神经原纤维tau已成为开发各种tauopathies的治疗的重点，包括 广告。 最近发现LRP1是tau摄取和扩散在大脑中的主调节器，表明 LRP1可能是减慢各种tauopathies进展的重要治疗靶标。诺沃 Bioscience正在开发针对LDL受体相关蛋白1（LRP1）的新型大分子疗法， tau摄取和扩散在大脑中的主调节器，以减缓诸如tauopathies的进展 （AD）并改善患者的功能结果。 Novoron的铅大院Novo-118是一个高亲和力的LRP1拮抗剂，可积极地进入大脑 通过皮下和静脉内给药。该提议的目的是评估 Novo-118的治疗潜力通过评估其限制tau在啮齿动物大脑中传播的能力。我们 将通过解开概念研究证明来实现这一目标，从而有效地限制了评估 从临床相关利用方面的转换性。为此，我们已经使用两个 主要目标：1）生成必要的概念证明，证明Novo-118消除Tau的能力 传播; 2）通过证明我们可以提供药物并在 临床翻译时尚。