Antisense oligonucleotide treatment for myotonic dystrophy

反义寡核苷酸治疗强直性肌营养不良

基本信息

批准号：
8241912
负责人：
CHARLES A THORNTON
金额：
$ 92.1万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8241912
关键词：
3&apos Untranslated Regions Affect Animal Model Antisense Oligonucleotides Biodistribution Cell Nucleus Cells Cessation of life Chemicals Chemistry Clinic Clinical Clinical Protocols Collaborations Complex Defect Development Development Plans Disease Disease Progression Dose Drug Kinetics Evaluation Event Functional RNA Functional disorder Gene Targeting Generations Genes Genetic Genetic Transcription Goals Human Inherited Institution Lead Macaca fascicularis Medical Messenger RNA Monkeys Mus Muscle Muscular Dystrophies Mutation Myocardium Myotonia Myotonic Dystrophy Neurons Nuclear Nucleic Acid Hybridization Patients Pharmaceutical Preparations Pharmacology Pharmacology and Toxicology Phase Phenotype Pilot Projects Plant Roots Process Protein Kinase RNA RNA Splicing RNA-Binding Proteins Rattus Regimen Regulation Research Personnel Ribonuclease H Rodent Safety Signal Pathway Skeletal Muscle Smooth Muscle Specificity Staging Subcutaneous Injections Symptoms Therapeutic Therapeutic Index Tissues Toxic effect Toxicology Transcript Transgenic Mice Wild Type Mouse base disability drug discovery effective therapy experience improved in vivo mouse model mutant pre-clinical premature protein activation public health relevance response skeletal stem subcutaneous uptake

项目摘要

DESCRIPTION (provided by applicant): Myotonic dystrophy type 1 (DM1) is a relatively common form of muscular dystrophy. The genetic basis is an expansion of CTG repeats in the 3' untranslated region of DMPK, a gene encoding a protein kinase expressed in skeletal, cardiac, and smooth muscle, and in neurons. This unusual mutation gives rise to RNA dominance, in which expression of RNA containing an expanded CUG (CUG^"'') repeat leads cell dysfunction. The mutant RNA accumulates in nuclear foci and initiates a complex cascade of downstream events, such as, defects in the regulation of RNA splicing. An attractive therapeutic approach, therefore, is to attack the problem at its root cause, by accelerating the clearance of the toxic RNA. To this end, we are proposing to develop RNase H-active antisense oligonucleotides (ASOs) targeting the mutant human DMPK {mut-hDMPK) mRNA. Previous studies have indicated that biodistribution and activity of ASOs in skeletal and candiac muscle is low. In contrast, we have found that systemically-delivered ASOs are highly active in muscle of wild-type mice, when targeted against a transcript that is retained in the nucleus - presumably because this is the compartment in which RNase H is active. We therefore postulated that CUG-expanded transcripts may also show efficient knockdown in muscle, because they also are retained in the nucleus. Consistent with this idea, subcutaneous administration of ASO for four weeks caused highly effective knockdown of CUG(R)"'' transcripts in muscle, reversal of RNA splicing derangements, and rescue of myotonia in transgenic mice. We seek now to develop optimally-effective, systemically-active ASOs that target mut- hDMPK transcripts for cleavage in skeletal and cardiac muscle. Development plans call for identification of ASOs that are highly active in cells, selection of ASOs that show optimal mut-hDMPK knockdown in transgenic mice, elimination of ASOs that show unacceptable toxicity in rodents and monkeys, and then IND- enabling toxicology/pharmacology studies using GMP-manufactured drug. To accomplish these goals we have formed an academic-commercial collaboration that includes all of the scientific, clinical, regulatory, and manufacturing expertise that is needed to bring a drug treatment for DM1 to the clinic. PUBLIC HEALTH RELEVANCE: Myotonic dystrophy is an inherited disease that causes progressive disability and premature death. No treatment is currently available that can improve the symptoms or slow the disease progression. The goal of this project is to develop a drug treatment for myotonic dystrophy.

描述（由申请人提供）：肌营养不良1型（DM1）是肌肉营养不良的一种相对常见的形式。遗传基础是DMPK的3'未翻译区域中CTG重复的扩展，DMPK的3'未翻译区域是一种编码在骨骼，心脏和平滑肌和神经元中表达的蛋白激酶的基因。这种异常的突变引起了RNA的优势，其中含有扩展的cug（cug^“''）重复的RNA表达会导致细胞功能障碍。突变的RNA在核重点中积累，并引发了复杂的下游事件的复杂级联，例如，在RNA的调节中，在RNA中的攻击，使其陷入困境。有毒的RNA。当针对保留在细胞核中的转录物时，大概是因为这是RNase H活性的隔室。 Consistent with this idea, subcutaneous administration of ASO for four weeks caused highly effective knockdown of CUG(R)"'' transcripts in muscle, reversal of RNA splicing derangements, and rescue of myotonia in transgenic mice. We seek now to develop optimally-effective, systemically-active ASOs that target mut- hDMPK transcripts for cleavage in skeletal and cardiac muscle. Development plans call for identification在细胞中高度活跃的ASO中，ASO在转基因小鼠中表现出最佳的MUT-HDMPK敲低，消除在啮齿动物和猴子中表现出不可接受的毒性的ASO，然后将毒理学/药理学研究分析，然后使用GMP型的目标进行了这些学术范围。需要将DM1的药物治疗带到诊所。公共卫生相关性：肌营养不良症是一种遗传性疾病，会导致进行性残疾和过早死亡。目前尚无治疗方法可以改善症状或减缓疾病进展。该项目的目的是为肌营养不良症开发药物治疗。