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：
8737980
负责人：
Qi L Lu
金额：
--
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 2015-07-31
项目状态：
已结题

项目摘要

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.

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 名活产男婴中就有 1 人受到影响。该疾病的特点是严重的肌肉萎缩和无力，在 3 至 5 岁之间临床上变得明显。 DMD 是由抗肌营养不良蛋白基因中所谓的移码突变引起的，导致过早终止且没有蛋白质合成，而 BMD 是由突变引起的，这些突变会产生截短但符合读框的转录本，其中含有部分或几乎全部功能的蛋白质。反义寡核苷酸 (AON) 介导的外显子剪接（反义疗法）已被证明可有效恢复因导致 DMD 的突变而破坏的开放阅读框。该项目 P.I.已经证实，通过在具有可耐受 7 毒性的动物模型中定期施用肽标记的吗啉代 AON (PPMO)，可以恢复并维持全身骨骼肌中接近正常水平的抗肌营养不良蛋白。我们还解决了将该疗法成功应用于临床的几个重要问题。开发可靠的 AON 选择体外系统使我们能够建立高效的 AON 作为针对单个外显子的特异性药物。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。该实验计划的重点是实现明确的里程碑：1）选择最有效的AON来靶向人类肌营养不良蛋白外显子45，去除该外显子可以治疗很大一部分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 PPMO 在动物模型中的功效以及所选 PPMO 在细胞培养物中的脱靶效应。 3）进行毒理学测试，从而可以向FDA提交研究性新药申请。反义疗法可有效治疗DMD动物模型，为治疗大多数DMD提供了现实的希望。我们的目标是将该疗法转化为临床试验。