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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在于脊髓中运动神经元的进行性丧失，导致僵硬、严重虚弱、骨骼肌萎缩，并最终在3 - 5年内死于呼吸衰竭。目前没有显著减缓疾病进展的疗法。在动物模型和ALS患者的样本中，我们发现了称为microRNA的小非编码RNA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这种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，我们打算将我们的研究结果转化为ALS的新疗法。公共卫生相关性：没有药物可以大大减缓ALS的进程。该应用的结果具有验证新的治疗靶点以及调节该靶点的方法的潜力。我们已经验证的microRNA靶点可能对ALS以外的其他神经退行性疾病也很重要，因此我们正在开发的miRNA抑制剂可能具有广泛的适用性。此外，我们正在开创性地在大脑和脊髓中使用miRNA的反义寡核苷酸抑制剂，这一技术可能对许多神经系统疾病具有治疗意义。