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

基本信息

批准号：
10679282
负责人：
KENNETH Stephen KOSIK
金额：
$ 11.03万
依托单位：
NOVORON BIOSCIENCE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10679282
关键词：
Active Biological Transport Affect Affinity Age Alzheimer&apos s Disease Amyloid beta-Protein Astrocytes Biological Availability Biological Sciences Blood - brain barrier anatomy Brain Bypass Cells Central Nervous System Agents Cytoskeletal Proteins Dementia Disease Disease model Dose Drug Delivery Systems Event Failure Future Goals Hour Human Impaired cognition In Vitro Investigation Ipsilateral LDL-Receptor Related Protein 1 Lead Measures Modeling Modification Nature Nerve Degeneration Neuraxis Neurofibrillary Tangles Neurons Outcome Outcome Measure Pathologic Pathology Patients Persons Pharmaceutical Preparations Physiological Population Process Reporting Risk Rodent Rodent Model Route Senile Plaques Subcutaneous Injections Tauopathies Technology Testing Therapeutic TimeLine Transgenic Model Translating Work abeta accumulation antagonist cell type clinically relevant clinically translatable design drug development functional outcomes human model improved in vivo intravenous administration intravenous injection novel novel strategies novel therapeutics overexpression pre-clinical preclinical development prevent receptor response subcutaneous success targeted treatment tau Proteins tau expression therapeutic target therapy development uptake vector

项目摘要

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。我们将通过取消概念研究证明的证明来实现这一目标，以进行有效的TAU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。