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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：
10327251
负责人：
KENNETH Stephen KOSIK
金额：
$ 34.96万
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 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10327251
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 Cleaved cell 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 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 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.

七、项目概要阿尔茨海默病 (AD) 是痴呆症最常见的原因，并且随着人口老龄化，这一问题日益严重。全球有超过 2500 万人患有痴呆症，其中大多数患有 AD。 AD的特点是不溶性淀粉样蛋白-β (Aβ) 斑块和过度磷酸化聚集体缠结的存在细胞骨架蛋白，tau。迄今为止，大多数 AD 治疗都针对 Aβ 聚集和斑块形成，但这些疗法在很大程度上未能从临床前啮齿动物模型转化为人类。有趣的是，头病理学已被证明与认知能力下降的相关性比 Aβ 更好，从而限制了疾病的传播神经原纤维 tau 蛋白已成为各种 tau 蛋白病治疗方法开发的日益关注的焦点，包括广告。最近发现 LRP1 是大脑中 tau 蛋白摄取和扩散的主要调节因子，这表明 LRP1可能是减缓各种tau蛋白病进展的重要治疗靶点。诺沃龙 Bioscience 正在开发针对 LDL 受体相关蛋白 1 (LRP1) 的新型大分子疗法，大脑中 tau 蛋白摄取和扩散的主要调节因子，可减缓 tau 蛋白病的进展，例如（AD）并改善患者的功能结果。 Novoron 的先导化合物 NOVO-118 是一种高亲和力 LRP1 拮抗剂，可被大脑主动吸收通过皮下和静脉内给药。本提案的目的是评估通过评估 NOVO-118 限制 tau 在啮齿动物大脑中扩散的能力来评估其治疗潜力。我们将通过将有效 tau 限制的概念验证研究与评估分开来实现这一目标临床相关利用方面的可翻译性。为了实现这一目标，我们设计了两个项目主要目标：1) 生成必要的概念证明，证明 NOVO-118 废除 tau 的能力传播; 2）通过证明我们可以提供药物并以一定的方式带来好处来降低技术风险临床可转化的时尚。