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

β 淀粉样蛋白和 Tau/糖胺聚糖双重抑制剂治疗阿尔茨海默病

基本信息

批准号：
10545235
负责人：
Paul Gregor
金额：
$ 98.39万
依托单位：
GISMO THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10545235
关键词：
3xTg-AD mouse AD transgenic mice Address Aging Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Amyloid Amyloid beta-Protein Amyloidosis Award Biochemical Biochemical Pathway Biological Assay Biological Availability Blinded Bone Marrow Brain Brain Diseases Canis familiaris Cardiovascular system Chemicals Chronic Cognitive Conscious Data Development Disease Dose Drug Kinetics Exhibits Family Caregiver Formulation GAG Gene Glycosaminoglycans Goals Half-Life Heparitin Sulfate Hepatocyte Hippocampus (Brain)Hour Human In Vitro Kentucky Knock-in Memory Loss Metabolic Methods Microsomes Modeling Monkeys Mus Mutagenicity Tests Nerve Degeneration Neuraxis Occupational Oral Pathogenesis Patients Peptides Pharmaceutical Preparations Pharmacologic Substance Pharmacology Phase Phase I Clinical Trials Plasma Positioning Attribute Process Property Rattus Recovery Risk Rodent Safety Seeds Series Small Business Innovation Research Grant Tauopathies Testing Therapeutic Toxic effect Toxicokinetics Toxicology Transgenic Mice Transgenic Organisms United States Universities Validation Work aged amyloid peptide base care costs chemical property cognitive performance efficacy evaluation family burden glycosaminoglycan receptor hyperphosphorylated tau improved inhibitor method development micronucleus mouse model nervous system disorder neuropathology novel physical property polysulfated glycosaminoglycan pre-clinical preclinical development preclinical evaluation preclinical study prion-like programs protein aggregation respiratory safety assessment scale up small molecule social standard of care tau Proteins tau interaction transgenic model of alzheimer disease β-amyloid burden

项目摘要

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.

抽象的该项目的目的是支持GTC-3295的IND申请以治疗阿尔茨海默氏病（AD）。 AD等神经退行性淀粉样蛋白疾病具有常见基本的生化途径导致淀粉样蛋白生成的寡聚和聚集淀粉样蛋白蛋白质种子在整个中枢神经中的肽和风雨状的传播系统（CNS）。最近的数据表明硫酸乙酰肝素糖胺聚糖（HS-GAGS）是负责内在化和扩散淀粉样蛋白β（ABETA）和TAU的受体大脑中的神经病理学。我们正在开发一种新颖的治疗疗法，糖胺聚糖相互作用的小分子（GISMOS），用于治疗AD。跨度是药物样的小分子化合物，抑制Abeta和Tau与HS-GAG的相互作用，每一个都是与AD发病机理有关的关键分子，可能会减少这些总蛋白质在阿尔茨海默氏症大脑中。 GTC-3295是一种新的化学实体（NCE）并且具有双重活性，因为它有效地抑制了Abeta以及与HS-的相互作用插科打。在先前在AD的转基因小鼠模型中的研究中，GTC-3295降低了淀粉样蛋白小鼠大脑的负担高达五倍，并显着减轻海马CA1区域的高磷酸化tau水平。最初的临床前研究表明 GTC-3295是一种口服，脑渗透剂具有有利的化合物体外ADME，药代动力学，毒性和其他研究的特性。这些结果提供了继续开发GTC-3295的理由。在这个SBIR项目中，我们将执行许多辅助临床前研究，包括两个物种中的GLP毒理学研究，扩展生物分析方法的合成，制定研究和开发。我们还将评估 GTC-3295在两种AD的转基因模型中的功效，分别解决Abeta和Tau 神经病理学。这些必要的开发活动的完成应定位成功提交FDA并进入I期临床的项目人类的审判。