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）：1 型强直性肌营养不良（DM1）是一种相对常见的肌营养不良形式。遗传基础是 DMPK 3' 非翻译区 CTG 重复的扩展，DMPK 是编码在骨骼、心脏、平滑肌和神经元中表达的蛋白激酶的基因。这种不寻常的突变产生了 RNA 优势，其中包含扩展的 CUG (CUG^"'') 重复序列的 RNA 的表达导致细胞功能障碍。突变的 RNA 在核灶中积累，并启动下游事件的复杂级联，例如缺陷因此，一种有吸引力的治疗方法是通过加速有毒 RNA 的清除来从根本上解决问题。为此，我们建议开发 RNase H 活性反义寡核苷酸。先前的研究表明，ASO 在骨骼肌和念珠肌中的生物分布和活性较低，相反，我们发现全身递送的 ASO 在肌肉中高度活跃。野生型小鼠，当针对保留在细胞核中的转录物时，可能是因为这是 RNase H 活跃的区室，因此我们假设 CUG 扩增。转录本也可能在肌肉中表现出有效的敲低，因为它们也保留在细胞核中。与这一想法一致，皮下注射 ASO 4 周，可高效敲低肌肉中的 CUG(R)"'' 转录本，逆转 RNA 剪接紊乱，并挽救转基因小鼠的肌强直。我们现在寻求开发最佳效果的药物，靶向 mut-hDMPK 转录物以在骨骼和心肌中裂解的系统活性 ASO 开发计划要求鉴定在细胞中高度活跃的 ASO，选择在转基因小鼠中表现出最佳 mut-hDMPK 敲低的 ASO，消除在啮齿动物和猴子中表现出不可接受的毒性的 ASO，然后使用 GMP 生产的药物进行 IND 毒理学/药理学研究为了实现这些目标，我们已经形成了一个学术商业项目。合作包括将 DM1 药物治疗推向临床所需的所有科学、临床、监管和制造专业知识。公共卫生相关性：强直性肌营养不良是一种遗传性疾病，会导致进行性残疾和过早死亡。目前尚无可以改善症状或减缓疾病进展的治疗方法。该项目的目标是开发一种治疗强直性肌营养不良的药物。