Development of an antisense oligonucleotide therapy for SOD1 Familial ALS

开发 SOD1 家族性 ALS 反义寡核苷酸疗法

基本信息

批准号：
9110459
负责人：
TIMOTHY M. MILLER
金额：
$ 14.48万
依托单位：
WASHINGTON UNIVERSITY
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 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9110459
关键词：
Acute Adult Amyotrophic Lateral Sclerosis Animal Model Animals Antisense Oligonucleotide Therapy Antisense Oligonucleotides Antisense Technology Base Pairing Binding Biological Assay Blood - brain barrier anatomy Brain C9ORF72 Cerebrospinal Fluid Cessation of life Clinic Clinical Clinical Trials Data Development Disease Disease Progression Dose Drug Kinetics Enzymes Failure Familial Amyotrophic Lateral Sclerosis Generations Genetic Grant Health Human In Vitro Inborn Genetic Diseases Inflammatory Intrathecal Injections Knowledge Lead Leukocytes Link Liquid substance Macaca Mediating Messenger RNA Motor Neurons Mus Muscular Atrophy Mutation Nerve Degeneration Neuraxis Neurodegenerative Disorders Nuclear Onset of illness Organ Pharmaceutical Preparations Pharmacologic Substance Pharmacology Phase Probability Proteins Rattus Research Respiratory Muscles Rodent Safety Saline Secondary to Spinal Cord Syndrome Testing Tissues Toxic effect Toxicogenetics Toxicology Transcript Work base cohort effective therapy efficacy testing experience gain of function human study in vivo lateral ventricle mutant neuroprotection next generation nonhuman primate peripheral blood pre-clinical ribonuclease H1 safety study superoxide dismutase 1 synthetic nucleic acid

项目摘要

DESCRIPTION (provided by applicant): Mutations in SOD1 cause approximately 2% of amyotrophic lateral sclerosis (ALS), an adult onset neurodegenerative disease characterized by loss of motor neurons resulting in severe weakness, muscle atrophy, and death typically in 3-5 years secondary to failure of respiratory muscles. Animal models and human studies suggest that lowering levels of SOD1 would be protective. We have developed antisense oligonucleotides that lower SOD1 in the brain and spinal cord when delivered to the cerebral spinal fluid. One of these antisense oligonucleotides was tested in a Phase I human clinical trial and demonstrated excellent safety at the low doses tested. However, it is clear from subsequent studies that we need to develop new antisense oligonucleotides for human SOD1. The collaborative work between Timothy Miller, Merit Cudkowicz and Isis Pharmaceuticals outlined in this grant will define a more potent, safer SOD1 antisense oligonucleotide by performing toxicology studies in rodents and non-human primates and by testing efficacy in the SOD1G93A rat studies. The successful completion of these studies will lead to an IND for the new SOD1 antisense oligonucleotide for SOD1-related ALS.

描述（由申请人提供）：SOD1中的突变导致大约2％的肌萎缩性侧索硬化症（ALS），这是一种成年发作神经退行性疾病，其特征是运动神经元丧失，导致严重的肌肉萎缩，肌肉萎缩，死亡通常在3-5岁的第二次因呼吸道肌肉失败而发生。动物模型和人类研究表明，降低SOD1水平将具有保护性。我们已经开发了反义寡核苷酸，该寡核苷酸降低了大脑中的SOD1和脊髓，当传递到大脑脊髓液中时。在I期人类临床试验中测试了这些反义寡核苷酸之一，并在测试的低剂量测试中表现出极好的安全性。但是，从随后的研究中可以明显看出，我们需要为人类SOD1开发新的反义寡核苷酸。蒂莫西·米勒（Timothy Miller），梅里特·库德科维奇（Morit Cudkowicz）和ISIS药品之间的合作工作将通过对啮齿动物和非人类灵长类动物进行毒理学研究以及在SOD1G93A RAT研究中测试效率来定义更有效，更安全的SOD1反义寡核苷酸。这些研究的成功完成将为SOD1相关ALS的新SOD1反义寡核苷酸提供IND。