Glycosaminoglycan Interacting Small Molecules (GISMO) as Novel AD Therapeutics

描述（由申请人提供）：本申请的目的是开发一种新型阿尔茨海默病（AD）治疗药物，其作用机制迄今未被探索。阿尔茨海默病是美国第六大死因，目前尚无治愈方法。患者家属和护理人员的负担是巨大的，每年的护理费用接近1万亿美元。阿尔茨海默病的过度紧张在很大程度上是由于缺乏有效的、创新的和改善疾病的治疗方案。阿尔茨海默病的一个突出病理特征是神经元溶酶体途径、内吞和自噬的强烈激活，这些障碍与溶酶体细胞毒性有关，是散发性阿尔茨海默病的早期表现之一。此外，溶酶体储存功能障碍和糖胺聚糖（GAGs）如硫酸肝素GAGs （HS-GAGs）的消化不良也是一些被称为粘多糖病的神经退行性疾病的主要原因。hs - gag与AD发病机制中涉及的关键分子，即-淀粉样蛋白（Abeta）， Tau和载脂蛋白e相互作用。我们的生物技术公司已经发现了一系列新的专有化合物，称为糖胺聚糖相互作用小分子（GISMO）。这些分子通过一种独特的作用机制来抑制蛋白质与hs - gag的相互作用，因此，代表了一种治疗AD的新方法。本提案的目标是开发一种新的AD治疗方法，通过内溶酶体途径抑制HS-GAG/ β蛋白聚集体的摄取。因此，GISMO化合物有望阻止hs - gag（与Abeta络合）的溶酶体储存，并保护神经细胞免受溶酶体功能障碍和细胞毒性的影响。此外，GISMO化合物还可以通过解离Abeta- gag复合物来分散已经聚集的与gag结合的Abeta，并减少细胞外Abeta的进一步积累。在这个项目中，具体目标1是评估24种已经确定的先导化合物的体外效力和安全性；具体目标2是执行先导优化，以提高安全性和选择性；特异性目的3是评估先导化合物的药代动力学特性，以鉴定脑渗透化合物。这些研究的成功完成将导致鉴定出三种优化的先导化合物，这些化合物将在AD动物模型中进行体内测试，随后的目标是确定用于ind研究的临床前候选药物。

DESCRIPTION (provided by applicant): The aim of this proposal is to develop a novel class of Alzheimer's Disease (AD) therapeutics acting via a hitherto unexplored mechanism of action. AD is the sixth-leading cause of death in the United States with no known cure. The burden on families and caregivers of patients is immense, with the annual cost of care approaching $1 trillion. The exorbitant strain of AD arises, in large part, to the lack of effective, innovative ad disease-modifying treatment options. A prominent pathological feature of AD is a robust activation of the neuronal lysosomal pathway, endocytosis and autophagy - disturbances of which are associated with lysosomal cytotoxicity and represent one of the earliest manifestations in sporadic AD. Furthermore, dysfunction in lysosomal storage and indigestibility of glycosaminoglycans (GAGs) such as heparan sulfate GAGs (HS-GAGs) is also the primary cause of several neurodegenerative diseases known as mucopolysaccharidoses. HS-GAGs interact with key molecules implicated in AD pathogenesis, i.e., ¿-amyloid (Abeta), Tau and Apolipoprotein E. Our biotechnology company has discovered a new series of proprietary compounds called Glycosaminoglycan-Interacting Small Molecule (GISMO). These molecules work via a unique mechanism of action to inhibit protein interactions with HS-GAGs, and as such, represent a novel therapeutic approach for the treatment of AD. The goal of this proposal is to develop a novel AD therapeutic that inhibits uptake of HS-GAG/Abeta protein aggregates via endo-lysosomal route. Consequently, GISMO compounds are expected to prevent lysosomal storage of HS-GAGs (complexed with Abeta) and protect nerve cells against lysosomal dysfunction and cytotoxicity. Furthermore, GISMO compounds may also dissipate already aggregated Abeta bound to GAGs and reduce further accumulation of extracellular Abeta, by dissociating the Abeta-GAG complexes. During this project, Specific Aim 1 is to evaluate 24 already identified lead compounds for in vitro potency and safety; Specific Aim 2 is to perform lead optimization to improve safety and selectivity; and Specific Aim 3 is to assess pharmacokinetic properties of lead compounds to identify brain-penetrant compounds. The successful completion of these studies will result in identification of three optimized lead compounds that will be subjected to in vivo testing in animal models of AD, with the subsequent aim of identifying a Preclinical Candidate for IND-enabling studies.