Amyloid-Beta and Tau/Glycosaminoglycan Dual Inhibitor for Alzheimer's Disease

摘要 该项目的目的是支持针对GTC-3295的IND应用程序，用于治疗 阿尔茨海默病(AD)。神经退行性淀粉样变性疾病，如阿尔茨海默病 导致淀粉样变性寡聚和聚集的潜在生化途径 淀粉样蛋白病态种子在中枢神经系统的多肽和蛋白样散布 系统(CNS)。最近的数据表明，硫酸乙酰肝素糖胺聚糖(HS-GAG)是 负责淀粉样β蛋白(Abeta)和tau内化和扩散的受体 大脑中的神经病理。我们正在开发一种新的治疗方法， 糖胺多糖相互作用的小分子(Gismos)，用于治疗AD。Gismos 是抑制Abeta和tau与HS-GAG相互作用的类药物小分子化合物， 其中每一个都是AD发病机制中的关键分子，并可能减少 这些聚集在阿尔茨海默氏症大脑中的蛋白质。GTC-3295是一种新的化学实体(NCE) 并具有双重活性，因为它有效地抑制了Abeta和Tau与HS- 恶作剧。在先前的阿尔茨海默病转基因小鼠模型研究中，GTC-3295减少了淀粉样蛋白 小鼠大脑中的负担增加了多达五倍，并显著降低 海马CA1区tau蛋白过度磷酸化水平。初步的临床前研究表明 GTC-3295是一种口服透皮制剂，具有良好的临床应用前景。 体外ADME性质、药代动力学、毒性等研究。这些结果提供了 继续开发GTC-3295的理由。在这个SBIR项目中，我们将执行一些 支持IND的临床前研究，包括两个物种的GLP毒理学研究，扩大规模 生物分析方法的合成、配方研究和发展。我们还将评估 GTC-3295在两种分别处理Abeta和tau的AD转基因模型中的作用 神经病理学。完成这些必要的开发活动后，应将 向FDA成功提交IND并进入I期临床的项目 在人体上进行试验。

ABSTRACT The aim of this project is to support an IND application for GTC-3295 for the treatment of Alzheimer's Disease (AD). Neurodegenerative amyloid diseases such as AD have common underlying biochemical pathways leading to oligomerization and aggregation of amyloidogenic peptides and prion-like spreading of amyloid proteopathic seeds throughout the Central Nervous System (CNS). Recent data suggest that heparan sulfate glycosaminoglycans (HS-GAGs) are the receptors responsible for internalization and spreading of amyloid-beta (Abeta) and tau neuropathologies in the brain. We are developing a novel class of therapeutics, Glycosaminoglycan-Interacting Small Molecules (GISMOs), for the treatment of AD. GISMOs are drug-like small molecule compounds that inhibit Abeta and tau interactions with HS-GAGs, each of which is a key molecule implicated in AD pathogenesis, and may reduce propagation of these aggregated proteins in the Alzheimer's brain. GTC-3295 is a New Chemical Entity (NCE) and has dual activity as it efficiently inhibits both Abeta as well as Tau interactions with HS- GAGs. In previous studies in a transgenic mouse model of AD, GTC-3295 decreased amyloid burden in the mouse brain by as much as five-fold, and significantly decreased hyperphosphorylated tau levels in CA1 region of hippocampus. Initial preclinical studies indicate that GTC-3295 is an orally available and brain penetrant compound possessing favorable properties in in vitro ADME, pharmacokinetics, toxicity and other studies. These results provide justification to continue developing GTC-3295. In this SBIR project, we will perform a number of IND-enabling preclinical studies including GLP Toxicology studies in two species, scale-up synthesis, formulation studies, and development of bioanalytical methods. We will also evaluate efficacy of GTC-3295 in two transgenic models of AD, that separately address Abeta and tau neuropathologies. Completion of these requisite development activities should position this project towards a successful IND submission to the FDA and advancing into Phase I clinical trials in humans.