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）：Duchenne肌肉营养不良（DMD）是最常见的肌肉营养不良形式，每3500个活着的男性出生中会影响1个。该疾病的特征是严重的肌肉浪费和无力，在3至5岁之间在临床上很明显。 DMD是由肌营养不良蛋白基因中所谓的移位突变引起的，导致过早终止，而无蛋白质合成，而BMD是由突变引起的，突变引起，这些突变造成截断，但框内转录本具有部分或几乎完全功能的蛋白质。反义寡核苷酸（AON）介导的外显子剪接（反义治疗）已被证明可有效恢复受到DMD突变中断的开放阅读框架。 P.I.项目已经确定了以下事实：在具有耐受性7毒性的动物模型中，可以定期给予肽标记的morpholino aon（PPMO），可以通过定期给药，可以恢复和维持近乎正常的肌蛋白水平的骨骼肌。我们还解决了几个重要的问题对于将治疗成功应用于诊所至关重要。用于AON选择的可靠体外系统的开发使我们能够建立高效的AON作为针对单个外显子的特定药物。我们已经定义了给药方案，因此可以在临床试验的最低毒性中实现治疗效果。在这个项目中/我们旨在将成功的实验疗法转化为DMD的临床治疗。实验计划以实现定义明确的里程碑为中心：1）选择最有效的AON来靶向人体肌营养不良蛋白外显子45，其去除可以治疗很大一部分DMD患者。通过既定的细胞培养系统将实现这一目标。 2）确定所选PPMO在动物模型中的疗效以及所选PPMO在细胞培养物中的脱靶效应。 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提供了现实的希望。我们旨在将治疗转化为临床试验。 公共卫生相关性：Duchenne肌肉营养不良（DMD）是一种常见且致命的遗传疾病，目前尚无治愈方法。反义疗法旨在挽救患病肌肉的功能，并为治疗大多数DMD提供了现实的希望。