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 阿尔茨海默病（AD）是痴呆症的最常见原因，并且随着人口老龄化而成为日益严重的问题。 全球有超过2500万人患有痴呆症，其中大多数患有AD。AD的特征 通过不溶性淀粉样蛋白β（Aβ）斑块的存在和过度磷酸化聚集体的缠结， 细胞骨架蛋白tau到目前为止，大多数AD治疗针对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到人类。有趣的是， 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 神经源性tau蛋白已经成为开发各种tau蛋白病的治疗的日益关注的焦点，包括 AD. 最近发现LRP 1是脑中tau摄取和扩散的主要调节剂，表明 LRP 1可能是减缓各种tau蛋白病进展的重要治疗靶点。诺沃龙 生物科学正在开发针对LDL受体相关蛋白1（LRP 1）的新型大分子疗法， 脑中tau摄取和扩散的主要调节剂，以减缓tau蛋白病的进展， (AD)并改善患者的功能结果。 Novoron的先导化合物NOVO-118是一种高亲和力的LRP 1拮抗剂，可被大脑积极吸收 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在啮齿类动物脑中扩散的能力，评估NOVO-118的治疗潜力。我们 为了实现这一点，将有效限制tau的概念验证研究与评估分开， 在临床相关应用方面的可翻译性。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消除tau蛋白的能力 传播; 2）通过证明我们可以提供药物并在一个特定的时间内获得收益来降低技术风险。 临床上可翻译的时尚。