How substrate dosage drives prion disease kinetics

底物剂量如何驱动朊病毒疾病动力学

基本信息

批准号：
10344724
负责人：
Sonia Minikel Vallabh
金额：
$ 59.24万
依托单位：
BROAD INSTITUTE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-01 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10344724
关键词：
Animal Model Antisense Oligonucleotides Biological Markers Biological Models Brain Cerebrospinal Fluid Complement Data Dependence Development Disease Disease Progression Engineering Foundations Future Genes Genetic Hamsters Human Infection Intercept Intervention Kinetics Knock-out Knowledge Lead Learning Light Mammals Measurement Microtus Modeling Molecular Mus Neurodegenerative Disorders Neurons Onset of illness Pathogenicity Pathologic Pathologic Processes Pathology Patients Pharmacology Phase Plasma PrP PrP gene Prion Diseases Prions Process Proteins Public Health Rattus Series Symptoms System Terminal Disease Testing Therapeutic Time Translating Work clinically relevant disorder control dosage experimental study human disease human model humanized mouse insight interest knockout animal mouse model neurofilament neurotoxicity novel postnatal pre-clinical prion seeds protein expression tool treatment response

项目摘要

PROJECT SUMMARY Prion disease is a uniquely rapid, universally fatal progressive neurodegenerative disease of humans and other mammals. It arises from a single protein, the native prion protein (PrP), which is capable of post-translationally misfolding into a self-templating and deadly “prion.” Genetic and pharmacological proofs of concept increasingly identify PrP dosage as the key to understanding, and ultimately intercepting this pathogenic cascade. In mice with genetically altered PrP levels, lower PrP levels lead to longer survival following prion infection, while excess PrP hastens disease. PrP-lowering antisense oligonucleotides (ASOs) now show promise as a potential therapeutic strategy. However, effective implementation will hinge on a deeper understanding of how PrP level controls the rates of prion nucleation, replication and neurotoxicity, and how this control translates across disease timepoints, species and strains. Though almost all human prion disease originates in the brain, PrP-lowering interventions have not yet been tested in spontaneous, rather than inoculated, prion models. Meanwhile, the magnitude of protection conveyed by 50% genetic PrP reduction can vary between model systems; the relative contributions of slowed prion replication and slowed neurotoxicity to observed survival benefit in different species and prion strains remain to be disentangled. Finally, PrP lowering must be studied in the context of patient-derived human prions, to assess how above learnings extrapolate to strains of public health interest. We will fill these gaps by assessing the following. 1) Kinetics of spontaneous prion formation. Using a new mouse model of spontaneous prion disease, we will track the spontaneously disease process through serial molecular measurements of neuronal damage and prion seeding activity. Through PrP-lowering tool compounds administered at different timepoints, we will disentangle how PrP dosage modulates prion formation, amplification, neurotoxicity and symptomatic progression. 2) Rapid and slow prion subtypes as a function of PrP dosage. Using newly engineered PrP knockout hamster and rat models, we will characterize the kinetics of pathological biomarker rise relative to disease onset and terminal illness as a function of PrP expression level in both canonically rapid (hamster) and more slowly progressive (rat) prion disease systems. 3) Impact of PrP lowering on human prions. Using a series of novel “humanized” mouse lines expressing human PrP at six different dosage levels, that have been shown susceptible to multiple clinically relevant human prion strains, we will characterize time to pathology, symptom onset, and terminal illness. PrP level will be varied on a lifelong basis through genetically manipulation, as well as through postnatal, precisely timed intervention with PrP-lowering tool compounds. Taken together, these studies will illuminate PrP’s control of disease kinetics across a spectrum of prion disease paradigms, while building a scientific foundation to guide future development of PrP-lowering therapeutics.

项目概要朊病毒病是一种独特的快速、普遍致命的人类和其他进行性神经退行性疾病它源自一种单一蛋白质，即天然朊病毒蛋白 (PrP)，它能够进行翻译后作用。错误折叠成一种自我模板化的致命“朊病毒”的概念的遗传和药理学证明。越来越多的人认为 PrP 剂量是了解并最终拦截这种致病性的关键在具有基因改变的 PrP 水平的小鼠中，较低的 PrP 水平导致朊病毒后存活时间更长。感染，而过量的 PrP 会加速疾病。然而，有效的实施将取决于更深入的治疗策略。了解 PrP 水平如何控制朊病毒成核、复制和神经毒性的速率，以及如何尽管几乎所有人类朊病毒疾病，这种控制都适用于疾病时间点、物种和菌株。由于 PrP 起源于大脑，因此降低 PrP 的干预措施尚未在自发试验中进行测试，而不是在自发试验中进行测试。同时，50% 的遗传 PrP 减少所带来的保护程度可以达到。模型系统之间存在差异；减慢朊病毒复制和减慢神经毒性的相对贡献在不同物种和朊病毒株中观察到的生存益处仍有待厘清。最后，PrP 降低。必须在源自患者的人类朊病毒的背景下进行研究，以评估上述知识如何推断我们将通过评估以下内容来填补这些空白：1）自发动力学。我们将使用一种新的自发性朊病毒病小鼠模型来追踪自发性朊病毒的形成。通过对神经损伤和朊病毒播种活性的一系列分子测量来了解疾病过程。通过在不同时间点施用降低 PrP 的工具化合物，我们将解开 PrP 如何剂量调节朊病毒的形成、扩增、神经毒性和症状进展 2) 快速和进展。使用新设计的 PrP 敲除仓鼠和大鼠，研究慢朊病毒亚型与 PrP 剂量的关系。模型中，我们将描述病理生物标志物相对于疾病发作和终末期上升的动力学疾病是典型快速进展（仓鼠）和更缓慢进展的 PrP 表达水平的函数（大鼠）朊病毒疾病系统 3) 使用一系列新型朊病毒降低 PrP 的影响。 “人源化”小鼠系以六种不同剂量水平表达人 PrP，已被证明对多种临床相关的人类朊病毒株敏感，我们将描述病理学、症状的时间发病和末期疾病的 PrP 水平也会通过基因操纵而在一生中发生变化。通过产后精确定时的干预，使用降低 PrP 的化合物综合起来，这些。研究将阐明 PrP 在一系列朊病毒疾病范式中对疾病动力学的控制，同时为指导降 PrP 疗法的未来发展奠定科学基础。