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（由适用提供）：该提案的目的是开发一种新型的阿尔茨海默氏病（AD）疗法，该疗法通过隐藏的意外作用机理起作用。 AD是美国没有已知治疗的第六个领先的死亡原因。对患者的家庭和看护人的烧伤是巨大的，年度护理费用接近1万亿美元。在很大程度上，由于缺乏有效的，创新的AD疾病改良治疗方案而产生的过高的AD菌株。 AD的一个突出的病理特征是神经元溶酶体途径，内吞作用和自噬的鲁棒性激活与溶酶体细胞毒性有关，并且代表了孢子体AD中最早的表现之一。此外，溶酶体储存功能障碍和糖胺聚糖（GAGS）（例如乙par）硫酸乙酰肝素GAGS（HS-GAGS）的差异性也是多种神经退行性疾病的主要原因。 HS-GAG与AD发病机理中实现的关键分子相互作用，即 - 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有化合物，称为糖胺糖糖果糖相关小分子（GISMO）。这些分子通过独特的作用机理来抑制蛋白质与HS-GAG的相互作用，因此代表了一种新型的AD治疗方法。该提案的目的是开发一种新型的AD疗法，该疗法通过内部溶酶体途径抑制HS-GAG/ABETA蛋白聚集体的摄取。因此，预计侧腔化合物可防止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的侵害。此外，通过解离Abeta-gag复合物，GISMO化合物还可以消散已汇总的Abeta，并降低了与插科打结合的ABETA，并减少了细胞外Abeta的进一步积累。在此项目中，特定目标1是评估24种已经确定的铅化合物，以实现体外效力和安全性；具体目标2是执行铅优化以提高安全性和选择性；具体目的3是评估铅化合物的药代动力学特性，以鉴定脑渗透剂化合物。这些研究的成功完成将导致鉴定出三种优化的铅化合物，这些化合物将在AD动物模型中进行体内测试，其目的是确定用于启用研究的临床前候选者。