A novel approach to restricting the spread of neurofibrillary tau

7.项目总结 阿尔茨海默病(AD)是痴呆症最常见的原因，随着人口老龄化，这是一个日益严重的问题。 全球有2500多万人患有痴呆症，其中大多数人患有阿尔茨海默病。广告的特点是 由于不溶性淀粉样β蛋白(Aβ)斑块的存在和过度磷酸化聚集体的缠绕 细胞骨架蛋白tau。到目前为止，大多数AD的治疗都是针对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的啮齿动物模型移植到人类身上。有趣的是，陶 已经证明，与β相比，病理与认知能力下降的相关性更好，从而限制了疾病的传播 神经原纤维tau已成为开发各种tauopy病治疗方法的日益关注的焦点，包括 广告。 最近发现，LRP1是tau在大脑中摄取和扩散的主要调节因子，表明 LRP1可能是减缓各种肌萎缩侧索硬化症进展的重要治疗靶点。诺沃隆 生物科学公司正在开发针对低密度脂蛋白受体相关蛋白1(LRP1)的新型大分子疗法， 在大脑中摄取和传播tau的主要调节器，以减缓tau病的进展，如 (Ad)并改善患者的功能结果。 Novoron的先导化合物Novo-118是一种高亲和力的LRP1拮抗剂，它被积极地吸收到大脑中 通过皮下和静脉给药。这项建议的目的是评估 Novo-118通过评估其限制tau在啮齿类动物大脑中传播的能力来实现治疗潜力。我们 将通过将有效的tau限制的概念验证研究与评估相分离来实现这一点 在临床相关用途方面的可译性。为了实现这一目标，我们设计了两个项目 主要目标：1)产生必要的概念证明，证明Novo-118有能力废除tau 传播；以及2)通过展示我们可以在 临床上可翻译的时尚。

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.