TRANSGENIC MOUSE MODELS FOR ASSESSING TREATMENTS OF PRION DISEASES

用于评估朊病毒疾病治疗的转基因小鼠模型

基本信息

批准号：
7447337
负责人：
STANLEY B PRUSINER
金额：
$ 26.77万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-06-15 至 2008-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7447337
关键词：
Accounting Acute Animals Anions Blood Blood - brain barrier anatomy Blood specimen Bos taurus Brain Cattle Cell Culture System Cells Cessation of life Clinical Clinical Research Creutzfeldt-Jakob Syndrome Cultured Cells Data Development Dextrans Disease Doctor of Medicine Dominant-Negative Mutation Dose Drug Design Endopeptidases Facility Construction Funding Category Functional disorder Human Immunoassay Inbred Strain Infection Investigation Isomerism Laboratory Study Lead Modeling Monitor Mouse Strains Mus Muscle Nervous system structure Neuroblastoma Neurodegenerative Disorders Numbers Pathologic Patients Peptide Hydrolases Pharmaceutical Preparations Preparation Prion Diseases Prions Protein Overexpression Publishing Quinacrine Quinacrine, (R)-Isomer Resistance Rodent Sampling Studies Scrapie Series Side Symptoms Taste Perception Testing Tetrapyrroles Therapeutic Thinking Time Toxic effect Transgenes Transgenic Organisms Treatment Protocols base combinatorial chemistry day dextran drinking water in vivo mouse model programs research study response

项目摘要

Prion diseases are neurodegenerative diseases of humans and animals, which are invariably fatal and lead to death within a year after onset of clinical symptoms. As with most other neurodegenerative diseases, no effective therapy is known. Potential therapeutics proposed for treatment of prion diseases include polysulfated anions, dextrans, and cyclic tetrapyrroles have been shown to increase survival time when given prior to prion infection in rodents, but not when given after infection has been initiated. Besides studies in rodents, mouse neuroblastoma (ScN2a) cells chronically infected with scrapie prions have been used to identify several candidate antiprion drugs but none of these drugs has been shown to be effective in halting prion diseases in either animals or humans. Based on recently published laboratory studies using cultured cells and a pilot clinical study in progress, we propose to perform a series of therapeutic-based experiments in transgenic (Tg) and non-Tg mice. Tg mice overexpressing (1) mouse (M) prion protein (PrP), (2) bovine (Bo) PrP or (3) a chimeric human-mouse PrP designated either MHu2M(M165V, E167Q) or MHu2M(M165V) will be used in these studies. Tg and non-Tg mice will be used to evaluate the toxicity of quinacrine isomers and a series of new compounds that are at least 10-fold more efficacious as determined in ScNa cells. After acute, short-term and longterm toxicity studies, treatment protocols for mice inoculated with prions will be initiated. Mice will begin to receive one of the quinacrine isomers or a new compound at point when 50%, 75% or 85% of the incubation time has elapsed. In most cases, the mice will be treated for 30 days. Two different strains of mouse or human prions will be used in these studies. Besides neuropathologic studies, samples of blood, muscle and brain will be taken for immunoassay determinations of PrP sc. The results of these studies are likely to provide important data leading toward the development of an effective therapeutic regimen for prion diseases in humans.

朊病毒病是人类和动物的神经退行性疾病，总是致命的，并导致临床症状出现后一年内死亡。与大多数其他神经退行性疾病一样，目前尚无有效的治疗方法。提议用于治疗朊病毒疾病的潜在疗法包括多硫酸化阴离子、葡聚糖和环状四吡咯，这些药物已被证明在啮齿动物感染朊病毒之前给予可延长存活时间，但在感染开始后给予则不然。除了啮齿类动物的研究外，慢性感染痒病朊病毒的小鼠神经母细胞瘤（ScN2a）细胞已被用来鉴定几种候选抗朊病毒药物，但这些药物都没有被证明能有效阻止动物或人类的朊病毒疾病。根据最近发表的使用培养细胞的实验室研究和正在进行的试点临床研究，我们建议在转基因（Tg）和非 Tg 小鼠中进行一系列基于治疗的实验。将使用过表达 (1) 小鼠 (M) 朊病毒蛋白 (PrP)、(2) 牛 (Bo) PrP 或 (3) 嵌合人-小鼠 PrP 的 Tg 小鼠，指定为 MHu2M(M165V、E167Q) 或 MHu2M(M165V)在这些研究中。 Tg 和非 Tg 小鼠将用于评估奎纳克林异构体和一系列新化合物的毒性，在 ScNa 细胞中测定这些化合物的有效性至少高 10 倍。经过急性、短期和长期毒性研究后，将启动对接种朊病毒的小鼠的治疗方案。当孵育时间经过 50%、75% 或 85% 时，小鼠将开始接受其中一种奎纳克林异构体或新化合物。在大多数情况下，小鼠将接受 30 天的治疗。这些研究将使用两种不同的小鼠或人类朊病毒株。除了神经病理学研究外，还将采集血液、肌肉和大脑样本，用于皮下 PrP 的免疫测定。这些研究的结果可能为开发人类朊病毒疾病的有效治疗方案提供重要数据。