Glycosaminoglycan Interacting Small Molecules (GISMO) as Novel AD Therapeutics

糖胺聚糖相互作用小分子 (GISMO) 作为新型 AD 疗法

• 批准号: 8591912
• 负责人: Paul Gregor
• 金额: $ 19.71万
• 依托单位: GISMO THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8591912
• 关键词: Acute; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Amyloid beta-Protein; Animal Model; Apolipoprotein E; Area Under Curve; Autophagocytosis; Binding; Bioavailable; Biological Assay; Biotechnology; Brain; Brain Diseases; Caring; Cause of Death; Cell Culture Techniques; Cell Line; Cell surface; Cells; Characteristics; Chemicals; Chronic; Cognitive; Complex; Disease; Drug Kinetics; Endocytosis Pathway; Evaluation; Exhibits; Family Caregiver; Functional disorder; Glycosaminoglycans; Goals; Half-Life; Hand; Heparin Binding; Heparitin Sulfate; Human; In Vitro; Incubated; Lead; Measures; Memory Loss; Mucopolysaccharidoses; Mus; Neurodegenerative Disorders; Neurologic; Neurons; Occupational; Pathogenesis; Patients; Performance; Pharmaceutical Preparations; Pharmacy (field); Phase; Plasma; Property; Proteins; Risk; Rodent; Route; Safety; Series; Small Business Innovation Research Grant; Structure; Testing; Therapeutic; Toxic effect; United States; Work; analog; base; cost; cytotoxicity; drug development; drug discovery; extracellular; high throughput screening; improved; in vitro Assay; in vivo; inhibitor/antagonist; innovation; lead series; neuroblastoma cell; neuroprotection; novel; novel therapeutic intervention; polysulfated glycosaminoglycan; pre-clinical; prevent; protein aggregate; public health relevance; research study; small molecule; social; standard of care; tau Proteins; uptake

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.

描述（由申请人提供）：本提案的目的是开发一种新型阿尔茨海默病（AD）治疗剂，其通过迄今为止未探索的作用机制发挥作用。AD是美国第六大死亡原因，没有已知的治愈方法。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。AD的过度紧张在很大程度上是由于缺乏有效的、创新的AD疾病修饰治疗选择。AD的一个突出病理特征是神经元溶酶体途径、内吞作用和自噬的强烈激活，其紊乱与溶酶体细胞毒性相关，并且代表散发性AD的最早表现之一。此外，溶酶体储存功能障碍和糖胺聚糖（GAG）如硫酸乙酰肝素GAG（HS-GAG）的消化不良也是称为粘多糖沉积症的几种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相互作用，即，β-淀粉样蛋白（Abeta）、Tau和载脂蛋白E。我们的生物技术公司发现了一系列新的专利化合物，称为糖胺聚糖相互作用小分子（GISMO）。这些分子通过独特的作用机制抑制蛋白质与HS-GAG的相互作用，因此代表了治疗AD的新治疗方法。该提案的目标是开发一种新型AD治疗剂，其通过内-溶酶体途径抑制HS-GAG/Abeta蛋白聚集体的摄取。因此，预期GISMO化合物防止HS-GAG（与Abeta复合）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。此外，GISMO化合物还可以通过解离Abeta-GAG复合物来消散已经聚集的与GAG结合的Abeta，并减少细胞外Abeta的进一步积累。在该项目中，具体目标1是评价24种已确定的先导化合物的体外效价和安全性;具体目标2是进行先导化合物优化，以提高安全性和选择性;具体目标3是评估先导化合物的药代动力学特性，以确定脑渗透化合物。这些研究的成功完成将导致三种优化的先导化合物的鉴定，这些化合物将在AD动物模型中进行体内试验，随后的目的是鉴定IND使能研究的临床前候选化合物。