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DEVELOPING A MICRORNA-TARGETED THERAPY FOR ALS

开发针对 ALS 的 MICRORNA 靶向疗法

基本信息

批准号：
8275481
负责人：
TIMOTHY M. MILLER
金额：
$ 33.25万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-15 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8275481
关键词：
Adult Affect Amyotrophic Lateral Sclerosis Animal Model Antisense Oligonucleotides Atrophic Binding Sites Brain Cell physiology Cessation of life Clinic Code Coupled Data Disease Disease Progression Disease model Dose Failure Functional RNA Genetic Transcription Grant Human Immunohistochemistry Inflammation Knock-out Knockout Mice Link Measures Messenger RNA Methods MicroRNAs Microglia Morphology Motor Neurons Mus Neuraxis Neurodegenerative Disorders Neuroglia Oligonucleotides Patients Pharmaceutical Preparations Phase I Clinical Trials Positioning Attribute Process Publishing Respiratory Failure Respiratory Muscles Rodent Model Sampling Skeletal Muscle Spinal Cord Sum Technology Testing Therapeutic Time Toxic effect Translating Translations Validation Work cell type chemokine cytokine design experience inhibitor/antagonist interest macrophage mouse model nervous system disorder new therapeutic target novel novel therapeutics therapeutic development therapeutic target tool

项目摘要

DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis is characterized by the progressive loss of motor neurons in the spinal cord, resulting in stiffness, severe weakness, atrophy of skeletal muscles, and eventual death from respiratory failure in 3-5 years. There are no current therapies that substantially slow the progression of the disease. In animal models and in samples from ALS patients, we have discovered changes in small non-coding RNA called microRNAs. We will now validate one particular microRNA as a therapeutic target and develop a method of inhibiting this microRNA using antisense oligonucleotides. We hypothesize that inhibition of this miRNA will substantially slow ALS in animal models. Given our current experience in Phase I trial using antisense oligonucleotides in ALS patients; we intend to translate our findings from this grant to a novel therapeutic for ALS. PUBLIC HEALTH RELEVANCE: There are no medications that substantially slow the course of ALS. The results of this application have the potential to validate a novel therapeutic target as well as a method of modulating that target. The microRNA target that we have validated is likely also important for other neurodegenerative diseases besides ALS and thus the miRNA inhibitor we are developing may be widely applicable. In addition, we are pioneering the use of antisense oligonucleotide inhibitors of miRNA in the brain and spinal cord, a technology that may have therapeutic implications for many neurological disorders.

描述（由申请人提供）：肌萎缩性侧索硬化症的特征是脊髓运动神经元的进行性丧失，导致僵硬、严重无力、骨骼肌萎缩，最终在3-5年内因呼吸衰竭而死亡。目前还没有能够显著减缓疾病进展的治疗方法。在动物模型和ALS患者的样本中，我们发现了小的非编码RNA（称为microRNAs）的变化。我们现在将验证一种特定的microRNA作为治疗靶点，并开发一种使用反义寡核苷酸抑制该microRNA的方法。我们假设在动物模型中，抑制这种miRNA将显著减缓ALS。鉴于我们目前在ALS患者中使用反义寡核苷酸的I期试验的经验；我们打算将我们的发现从这项资助转化为一种新的治疗ALS的方法。