Antisense therapy for DMD-Optimization and toxicology of AON for exon 45 skipping

DMD 反义治疗-外显子 45 跳跃的 AON 优化和毒理学

基本信息

批准号：
7942831
负责人：
Qi L Lu
金额：
$ 48.88万
依托单位：
CAROLINAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2013-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7942831
关键词：
Address Affect Age Animal Model Antisense Oligonucleotides Birth Cell Culture System Cell Culture Techniques Chemistry Clinic Clinical Treatment Clinical Trials Development Disease Drug Kinetics Duchenne muscular dystrophy Dystrophin Excision Exons Frameshift Mutation Future Genes Goals Hereditary Disease Human In Vitro Individual Injection of therapeutic agent Introns Investigational New Drug Application Investigational Therapies Life Mediating Mus Muscle Muscular Dystrophies Mutation Myoblasts Myocardium Open Reading Frames Patients Peptides Pharmaceutical Preparations Phase Protein Biosynthesis Proteins RNA Splicing Reporter Research Reverse Transcriptase Polymerase Chain Reaction Screening procedure Skeletal Muscle System Testing Therapeutic Therapeutic Effect Toxic effect Toxicology Transcript Translating Treatment Efficacy Treatment Protocols base effective therapy genome-wide male pre-clinical premature programs restoration skeletal wasting

项目摘要

Title: Antisense therapy for DMD-Optimization and toxicology of AON for exon 45 skipping. Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy affecting 1 in every 3500 live male births. The disease is characterized by severe muscle wasting and weakness, which becomes clinically evident between the ages of 3 to 5 years. DMD is caused by so called frame-shift mutations in the dystrophin gene leading to premature termination with no protein synthesis whereas BMD is caused by mutations which create truncated, but in-frame transcripts with proteins of partial or nearly full function. Antisense oligonucleotide (AON)-mediated exon splicing (antisense therapy) has been shown to be effective for restoration of the open reading frame disrupted by mutations that cause DMD. The project P.I. has established the facts that near normal levels of dystrophin can be restored and maintained in the body-wide skeletal muscles through regular administration of a peptide-tagged morpholino AON (PPMO) in animal models with tolerable ¿ toxicity. We have also addressed several important issues critical for successful applications of the therapy to clinics. The development of a reliable in vitro system for AON selection enables us to establish highly effective AONs as specific drugs to target individual exons. We have defined the regimen of administration so therapeutic effect can be achieved with minimum toxicity for clinical trial. In this project/we aim to translate the successful experimental therapy to clinical treatment of DMD. The experimental plan is centered to achieve well-defined milestones: 1) Select most efficacious AON for targeting human dystrophin exon 45, the removal of which can treat a large proportion of DMD patients. This aim will be achieved with eatablished cell culture systems. 2) Determine the efficacy of selected PPMOs in animal models ahd off-target effects of the selected PPMOs in cell cultures. 3) Conduct toxicology tests, thus an investigational new drug application can be submitted to the FDA. Antisense therapy is effective in treating animal models of DMD and provides a realistic hope for treating the majority of DMD. We aim to translate the therapy into clinical trials.

标题：用于EON EXON 45跳过的DMD优化和毒理学的反义疗法。 Duchenne肌肉营养不良（DMD）是影响每3500中1的肌肉营养不良的最常见形式活着的男性出生。该疾病的特征是严重的肌肉浪费和无力，在临床上变成在3至5岁之间的证据。 DMD是由肌营养不良蛋白中所谓的移位突变引起的基因导致过早终止，没有蛋白质合成，而BMD是由突变引起的创建具有部分或几乎完整功能的蛋白质的截短，但框内转录本。反义寡核苷酸（AON）介导的外显子剪接（反义疗法）已被证明对恢复开放式阅读框架被导致DMD的突变中断的恢复。 P.I.项目已经建立了可以在整个身体骨骼肌肉中恢复并维持接近正常肌营养不良蛋白水平的事实通过在动物模型中定期给予肽标记的莫夫利诺群岛AON（PPMO）。毒性。我们还解决了几个重要的问题，对于该治疗的成功应用至关重要诊所。为AON选择的可靠体外系统的开发使我们能够建立非常有效的 AON作为针对单个外显子的特定药物。我们已经定义了管理方案SO治疗临床试验的最小毒性可以实现效果。在这个项目中/我们旨在翻译成功 DMD临床治疗的实验疗法。实验计划以实现明确的定义为中心里程碑：1）选择靶向人肌营养不良蛋白外显子45的最有效的AON，其去除可以治疗大部分DMD患者。饮食细胞培养系统将实现这一目标。 2）确定所选PPMO在动物模型中的有效性AHD AHD脱靶效应在细胞中的靶向效应文化。 3）进行毒理学测试，因此可以将研究性的新药应用提交给FDA。反义疗法可有效治疗DMD的动物模型，并为治疗大多数DMD。我们旨在将治疗转化为临床试验。