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Synthetic biomarkers of RNA modulation therapies

RNA 调节疗法的合成生物标志物

基本信息

批准号：
8841572
负责人：
Thurman M Wheeler
金额：
$ 36.88万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8841572
关键词：
Address Adopted Adult Alternative Splicing Animal Model Antisense Oligonucleotides Biological Assay Biological Markers Cell Therapy Cells Clinical Clinical Trials Complement Custom Data Detection Development Disease Dose Drug Monitoring Engineering Exclusion Exons Fluorescence Fluorescence Microscopy Fluorescence Spectroscopy Fluorometry Future Genetic Transcription Goals Guidelines Hereditary Disease Human Image Imaging Techniques Immunohistochemistry In Situ In Vitro Inborn Genetic Diseases Injury Intramuscular Injections Lentivirus Vector Life Measurement Microscopy Modeling Modification Mus Muscle Muscle Cells Muscular Dystrophies Myotonic Dystrophy Natural regeneration Non-Invasive Cancer Detection Outcome Patients Pattern Pharmaceutical Preparations Preclinical Drug Evaluation RNA RNA Splicing Regulation Reporter Reporting Reproducibility Reverse Transcriptase Polymerase Chain Reaction Sensitivity and Specificity Signal Transduction Spectrum Analysis Speed System Testing Therapeutic Time Toxic effect Transcript Transgenic Mice Transgenic Organisms Translating Translations Western Blotting adeno-associated viral vector base candidate identification design drug candidate drug discovery effective therapy fluorescence imaging high throughput screening imaging modality in vivo in vivo imaging minimally invasive mouse model myotonic dystrophy protein kinase novel novel strategies protein expression public health relevance research study screening therapeutic development

项目摘要

DESCRIPTION (provided by applicant): This proposal addresses a matter of key importance for drug discovery: development of biomarkers that monitor drug effects in vivo. We focus on myotonic dystrophy (dystrophia myotonica) type 1 (DM1), the most common muscular dystrophy in adults. DM1 is a dominantly inherited disorder caused by expression of DM protein kinase (DMPK) transcripts that contain an expanded CUG repeat (CUGexp). A well-understood consequence of CUGexp RNA expression includes mis-regulation of alternative splicing ("RNA toxicity"). In DM1 mouse models, therapeutic antisense oligonucleotides induce correction of alternative splicing patterns through modulation of CUGexp RNA toxicity. We, and others, are screening for endogenous biomarkers of disease activity and drug effect. In this proposal, we adopt an alternative approach by engineering novel biomarkers that enable non-invasive or minimally invasive detection, within minutes, of whether new treatments are having their intended effect. Our overall strategy involves the use of non-invasive fluorescence measurements to identify in vivo correction of alternative splicing in live DM1 mouse models. Efforts will include development of a high throughput in vivo screening assay to identify candidate drugs. The ultimate goal is to develop novel biomarkers that enable rapid identification of drug effects, demonstrate minimal toxicity, speed throughput of drug discovery, and, with modification, will translate to patients. Our approach will have broad application for genetic disorders beyond DM1 that are candidates for RNA modulation therapies.

描述（由申请人提供）：该提案解决了药物发现的关键重要性问题：开发体内监测药物作用的生物标志物。我们专注于强直性肌营养不良症（dystrophicamyotonica）1型（DM1），成人中最常见的肌营养不良症。DM 1是一种显性遗传性疾病，由DM蛋白激酶（DMPK）转录物表达引起，该转录物含有扩展的CUG重复序列（CUGexp）。CUGexp RNA表达的一个众所周知的后果包括可变剪接的错误调节（“RNA毒性”）。在DM1小鼠模型中，治疗性反义寡核苷酸通过调节CUGexp RNA毒性诱导可变剪接模式的校正。我们和其他人正在筛选疾病活动和药物作用的内源性生物标志物。在这项提案中，我们采用了一种替代方法，通过设计新的生物标志物，使非侵入性或微创检测，在几分钟内，新的治疗方法是否有其预期的效果。我们的总体策略包括使用非侵入性荧光测量来确定在活体DM1小鼠模型中的选择性剪接的体内校正。努力将包括开发一种高通量的体内筛选试验，以确定候选药物。最终目标是开发新的生物标志物，能够快速识别药物作用，表现出最小的毒性，加快药物发现的通量，并通过修改，将转化为患者。我们的方法将广泛应用于DM 1以外的遗传疾病，这些疾病是RNA调节疗法的候选者。