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

• 批准号: 7731707
• 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
• 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/7731707
• 关键词: Antisense; therapy; DMD; Optimization; toxicology

DESCRIPTION (provided by applicant): 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 7 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 established cell culture systems. 2) Determine the efficacy of selected PPMOs in animal models and 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. PUBLIC HEALTH RELEVANCE: Duchenne muscular dystrophy (DMD) is a common and fatal genetic disease and there is no cure currently. Antisense therapy aims to rescue the functions of diseased muscles and provides a realistic hope for treating the majority of DMD.

描述（由申请人提供）：杜氏肌营养不良症（DMD）是最常见的肌营养不良症，每3500例活产男婴中就有1例受影响。这种疾病的特征是严重的肌肉萎缩和虚弱，在3至5岁之间临床上变得明显。DMD是由肌营养不良蛋白基因中的所谓移码突变引起的，导致过早终止而没有蛋白质合成，而BMD是由突变引起的，该突变产生截短的但符合读框的转录物，其中蛋白质具有部分或几乎全部功能。反义寡核苷酸（AON）介导的外显子剪接（反义治疗）已被证明是有效的恢复开放阅读框架破坏的突变，导致DMD。P.I.项目已经确定了这样的事实，即通过在动物模型中定期施用肽标记的吗啉代AON（PPMO），可以在全身骨骼肌中恢复和维持接近正常水平的肌营养不良蛋白，并且具有可耐受的毒性。我们还讨论了几个重要的问题，成功的临床应用的治疗。开发一个可靠的体外系统AON选择使我们能够建立高效的AON作为特定的药物，以靶向个别外显子。我们已经确定了给药方案，以便在临床试验中以最小的毒性达到治疗效果。在这个项目中，我们的目标是将成功的实验疗法转化为DMD的临床治疗。实验计划的重点是实现明确的里程碑：1）选择最有效的AON来靶向人肌营养不良蛋白外显子45，去除该外显子可以治疗大部分DMD患者。这一目标将通过已建立的细胞培养系统来实现。2)确定所选PMOs在动物模型中的功效以及所选PMOs在细胞培养物中的脱靶效应。3)进行毒理学测试，从而可以向FDA提交研究性新药申请。反义治疗对DMD动物模型的治疗是有效的，为治疗大多数DMD提供了现实的希望。我们的目标是将这种疗法转化为临床试验。 公共卫生相关性：杜氏肌营养不良症（DMD）是一种常见和致命的遗传性疾病，目前没有治愈方法。反义治疗的目的是挽救病变肌肉的功能，为治疗大多数DMD提供了现实的希望。