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A Novel Drug Candidate for the Treatment of Huntington's Disease

治疗亨廷顿病的新候选药物

基本信息

批准号：
9751981
负责人：
Pamela Anne Maher
金额：
$ 24.05万
依托单位：
SALK INSTITUTE FOR BIOLOGICAL STUDIES
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9751981
关键词：
Address Affect Age Age-Months Alzheimer&apos s disease model Animal Disease Models Animal Model Animals Anti-inflammatory Antioxidants Bioinformatics Biological Biological Assay Brain Clinic Clinical Trials Cognition Complex Complications of Diabetes Mellitus Corpus striatum structure Defect Disease Disease Progression Disease model Dose Excision Exhibits Flavonols Funding Gene Expression Gene Expression Profiling Genes Genetic Transcription Goals Human Huntington Disease In Vitro Investigational Drugs Ischemic Stroke Length Longevity Medical Mendelian disorder Mitochondria Modeling Molecular Target Monitor Motor Mus Mutation Neurodegenerative Disorders Neurons Onset of illness Oral Pathologic Pathology Pathway interactions Patients Pharmaceutical Preparations Pharmacology Physiological Plasma Prevention Prevention strategy Preventive Procedures Property Safety Series Stress Symptoms Technology Testing Therapeutic Therapeutic Studies Time Toxic effect Toxicology Transgenic Organisms Treatment Efficacy aged base chemical property clinical candidate disorder control drug candidate drug discovery experimental study fisetin fly improved in vitro Model mouse model neuron loss neurotoxicity novel therapeutics pre-clinical prevent protein aggregate response therapeutic evaluation transcription factor transcriptome sequencing

项目摘要

There are currently no drugs that reverse or halt the progression of Huntington's disease (HD). Moreover, drug candidates against a single molecular target have failed. Therefore, a different approach to HD drug discovery is needed. Herein the hypothesis is tested that a compound that modulates a large set of HD-related targets will be effective against the disease. The rare flavonol fisetin induces transcription factors for neuroprotective and antioxidant genes, maintains ATP levels in stressed nerve cells, enhances the removal of intracellular aggregated proteins and is a potent anti-inflammatory compound. Fisetin has proven efficacy in mouse and fly models of Huntington's (Hum. Mol. Gen. 20:261, 2011). It is also effective in animal models of Alzheimer's disease, ischemic stroke, and the CNS complications of diabetes, all of which share some pathological features with HD. Potent derivatives of fisetin with improved pharmacology were made that maintain its multiple biological activities (J. Med. Chem. 55:378, 2012). From 150 synthetic fisetin derivatives, one has been selected for further study in the context of HD based on pharmacological parameters and the prevention of HD neurotoxicities in vitro. CMS121 is effective in eleven in vitro models that define most of the known brain toxicities associated with HD as well as in two different mouse models of AD. In addition, CMS121 has excellent ADME, safety, and pharmacological properties. Funds are independently being sought for Investigational New Drug (IND) toxicology studies for the use of CMS-121 for the treatment of AD. If it were possible to demonstrate therapeutic efficacy in HD mouse models, then CMS- 121 could be sped to the clinic for the treatment of HD. Therefore, the two Specific Aims of this application are to test the therapeutic efficacy of CMS121 in 4 well-established mouse models of HD and at the same time examine the striatal gene expression relationship between these models and drug effects. The R6/2 mice in which fisetin is effective will be used for initial dosing studies. These experiments will be followed by N171-82Q animals that have a slower disease onset and the YAC128 model that expresses full-length hHTT, have a normal life span, but exhibit motor defects at 6 mo and have more human-like pathology. Finally, a therapeutic study will be done in which the drug candidate is given to YAC128 mice that are symptomatic. Changes in striatal gene expression in each will be assayed to define the relationship between the four models and their drug responses. At the end of two years, CMS121 will have been tested in multiple rigorous animal models of HD and a greater understanding of the physiological relationship between these models will have been gained. This will provide an excellent test of an alternative approach to the current drug discovery paradigm for HD that is based on preselected single targets. Most importantly, because of its exceptional neuroprotective activities, good medical chemical properties, and the excellent safety profile, CMS121 will be a very strong clinical candidate for HD treatment.

目前还没有药物可以逆转或阻止亨廷顿病（HD）的进展。此外，针对单一分子靶点的候选药物也失败了。因此，一种不同的方法需要HD药物发现。在本文中，假设被测试，即调节一大组代谢物的化合物是一种化合物。 HD相关靶点将有效对抗该疾病。稀有黄酮醇非瑟酮诱导转录因子神经保护和抗氧化基因，维持紧张的神经细胞中的ATP水平，清除细胞内聚集的蛋白质，是一种有效的抗炎化合物。非瑟酮已经证明在亨廷顿氏病小鼠和苍蝇模型中的功效（图10）。摩尔Gen. 20：261，2011）。对动物也有效阿尔茨海默病、缺血性中风和糖尿病的中枢神经系统并发症的模型，所有这些模型都有 HD的一些病理特征。有效的衍生物的非瑟酮与改进的药理学维持其多种生物活性（J. Med. Chem. 55：378，2012）。从150合成非瑟酮衍生物，一个已被选定为进一步研究的背景下，HD的基础上药理学参数和体外HD神经毒性的预防。CMS 121在11种体外模型中有效定义了大多数已知的与HD相关的脑毒性，以及在两种不同的小鼠模型中， AD.此外，CMS 121具有优异的ADME、安全性和药理学特性。资金正在寻求独立的研究性新药（IND）毒理学研究，用于CMS-121用于 AD的治疗。如果有可能在HD小鼠模型中证明治疗功效，那么CMS- 121例患者可迅速送往门诊治疗HD。因此，本申请的两个具体目的在4种良好建立的HD小鼠模型中测试CMS 121的治疗功效，时间检测这些模型与药物作用之间纹状体基因表达的关系。R6/2 非瑟酮有效的小鼠将用于初始给药研究。这些实验之后，具有较慢疾病发作的N171- 82 Q动物和表达全长的YAC 128模型 hHTT具有正常寿命，但在6个月时表现出运动缺陷，并具有更像人类的病理学。最后，将进行治疗研究，其中将候选药物给予YAC 128小鼠，症状。将分析每个个体纹状体基因表达的变化，以确定四种模型及其药物反应。两年后，CMS 121将在多个国家进行测试。严格的HD动物模型和更好地了解这些之间的生理关系，将获得模型。这将是一个很好的测试替代方法，目前 HD的药物发现范例是基于预先选择的单一靶点。最重要的是，由于其卓越的神经保护活性、良好的医用化学性质和优异的安全性， CMS 121将是HD治疗的非常强的临床候选药物。