Long-Term Safety, Efficacy, and Mechanism of PERK Inhibition Therapy for Prion Disease

PERK 抑制疗法治疗朊病毒病的长期安全性、有效性和机制

• 批准号: 9268578
• 负责人: Surachai Supattapone
• 金额: $ 20.25万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9268578
• 关键词: Address; Adverse effects; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Animal Welfare; Astrocytes; Beta Cell; Bioavailable; Biological Assay; Brain; Brain Diseases; Brain Injuries; Characteristics; Clinical; Clinical Trials; Communicable Diseases; Creutzfeldt-Jakob Syndrome; Diet; Disease; Disease Progression; Disease model; Economic Burden; Effectiveness; Enterobacteria phage P1 Cre recombinase; Eukaryotic Initiation Factors; Evaluation; Functional disorder; Goals; Human; Hyperglycemia; Individual; Infection; Inherited; JAK1 gene; Knock-out; Knockout Mice; Laboratory Infection; Longitudinal Studies; Mediating; Medical; Medical Economics; Membrane; Methods; Microglia; Modeling; Molecular Conformation; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Oral; Oral Administration; PERK kinase; Parkinson Disease; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Phosphoric Monoester Hydrolases; Phosphorylation; Play; PrP; PrPSc Proteins; Prion Diseases; Prions; Process; Prophylactic treatment; Protein Biosynthesis; Protein Isoforms; Protein-Serine-Threonine Kinases; Proteins; Reporting; Rodent; Role; STAT3 gene; Safety; Stress; Structure of beta Cell of islet; Symptoms; Tamoxifen; Testing; Therapeutic; Time; Tissues; Toxic Actions; Toxic effect; Transgenic Mice; United States; astrogliosis; cell type; cost effective; effective therapy; experimental study; inhibitor/antagonist; misfolded protein; neuroinflammation; neuron loss; novel therapeutics; overexpression; premature; prevent; promoter; protein misfolding; response

Project Summary Background There are currently no therapies that can stop the process of neuronal degeneration in diseases associated with protein misfolding such as prion disease, Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis (ALS). Recent studies suggest that the kinase PERK, a critical regulator of the unfolded protein response (UPR), triggers both neurodegeneration and neuroinflammation in response to protein misfolding. GSK2606414, an orally bioavailable PERK inhibitor, successfully delayed the progression of infectious prion disease in mice over a 3-week observation period even when administered after the onset of symptoms (9/9 mice treated with the drug survived prion infection, while 0/17 untreated mice died). However, this promising drug inhibits PERK in pancreatic β-cells as well as the brain, and so causes hyperglycemia as a side effect. Although hyperglycemia can be easily managed in humans, it is much more difficult to control in experimental mice, and therefore the trial had to be abandoned after three weeks. Consequently we do not know whether inhibiting PERK could successfully treat prion disease for extended periods of time in mice. This information is critical before planning clinical trials of the drug in humans. Proposed Experiments In Specific Aim 1, we will use transgenic mice expressing tamoxifen-inducible CRE recombinase under the control of the Thy1 promoter to knock out PERK in all neurons, but not in pancreatic β-cells. Hyperglycemia will not occur, and therefore we will be able to complete the extended trial of PERK inhibition that could not be completed before. We will determine the long-term safety of PERK inhibition, and its efficacy in the treatment of prion infection in mice. This study will show whether anti- PERK drugs have potential for use as a long-term treatment for prion diseases, and potentially as long-term prophylaxis in individuals with familial prion disease. Our approach represents a cost- effective and time-efficient way to answer these important questions. In Specific Aim 2, we will use transgenic mice with PERK selectively knocked out of astrocytes and microglia to determine whether PERK-mediated neuroinflammation also contributes to the mechanism of neuronal death in prion disease. In summary, our experiments will provide important information about the safety, effectiveness, and mechanism of PERK inhibition as a long-term therapy against neurodegeneration.

项目摘要 背景 目前还没有治疗方法可以阻止疾病中神经元变性的过程 与蛋白质错误折叠相关的疾病，如朊病毒病，阿尔茨海默病，帕金森病， 和肌萎缩侧索硬化症（ALS）。最近的研究表明，激酶PERK，一个关键的 未折叠蛋白反应（UPR）的调节因子，触发神经变性和 神经炎症反应蛋白质错误折叠。GSK 2606414，一种口服生物可利用的PERK 抑制剂，成功地延缓了小鼠感染性朊病毒疾病的进展超过3周 即使在症状发作后给药时，观察期内也是如此（9/9只用 药物在朊病毒感染中存活，而0/17未治疗的小鼠死亡）。然而，这种有前途的药物抑制了 PERK在胰腺β细胞以及大脑中，因此导致高血糖症作为副作用。 虽然高血糖症在人类中可以容易地控制，但在糖尿病患者中控制高血糖症要困难得多。 实验小鼠，因此试验不得不在三周后放弃。因此我们 我不知道抑制PERK是否可以长期成功治疗朊病毒病 时间在老鼠这些信息在计划该药物的人体临床试验之前至关重要。 拟议实验 在特定目标1中，我们将使用表达他莫昔芬诱导型CRE重组酶的转基因小鼠 在Thy 1启动子的控制下敲除所有神经元中的PERK，但不敲除胰腺β细胞中的PERK。 不会出现hyperplasia，因此我们将能够完成PERK的扩展试验 以前无法完成的抑制。我们将确定PERK的长期安全性 抑制，以及其在治疗小鼠朊病毒感染中的功效。这项研究将表明， PERK药物有可能用作朊病毒疾病的长期治疗， 家族性朊病毒病患者的长期预防。我们的方法是有代价的- 有效和及时的方式来回答这些重要的问题。在具体目标2中，我们将使用 选择性敲除星形胶质细胞和小胶质细胞的PERK转基因小鼠， PERK介导的神经炎症也有助于朊病毒中神经元死亡的机制 疾病总之，我们的实验将提供有关安全性的重要信息， 有效性和PERK抑制作为抗神经变性的长期疗法的机制。

项目成果

CAG Expansions Are Genetically Stable and Form Nontoxic Aggregates in Cells Lacking Endogenous Polyglutamine Proteins.

CAG 扩增具有遗传稳定性，并在缺乏内源性聚谷氨酰胺蛋白的细胞中形成无毒聚集体。

• DOI: 10.1128/mbio.01367-16
• 发表时间: 2016
• 期刊: mBio
• 影响因子: 6.4
• 作者: Zurawel,AshleyA;Kabeche,Ruth;DiGregorio,SonjaE;Deng,Lin;Menon,KartikeyaM;Opalko,Hannah;Duennwald,MartinL;Moseley,JamesB;Supattapone,Surachai
• 通讯作者: Supattapone,Surachai