Pediatric toxicity and efficacy in long-term systemic treatment with anti-sense

反义药物长期全身治疗的儿科毒性和疗效

• 批准号: 8246746
• 负责人: JOHANNES NICOLAAS VAN DEN ANKER
• 金额: $ 87.62万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-26 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8246746
• 关键词: Pediatric; toxicity; efficacy; long; term

DESCRIPTION (provided by applicant): Duchenne muscular dystrophy is the most common monogenic pediatric inborn error, affecting one in 3,500 live born males world-wide. The most promising molecular therapeutic approach for DIVID is systemic delivery of anti-sense oligonucleotides (AOs), where the drugs alter mRNA splicing, and converting out-of-frame loss-off function transcripts to in-frame transcripts capable of producing semi-functional (Becker-like) dystrophin. In the large animai (dog) model of Duchenne dystrophy, we have shown that intravenous (iV) delivery of high dose morpholino AOs is able to rescue dystrophin protein production to about 20% of wild-type levels, and cause stabilization or improvement of multiple functional, histological, and imaging outcome measures (Yokota et al. 2009). Initial human clinical trials using morpholino AO directed at exon 51 have shown that both direct intramuscular injection and IV administration can result in de novo dystrophin production. However, it is anticipated that repeated doses of 20 mg/kg - 100 mg/kg are likely required for sustained efficacy. GLP toxicity studies in mice and non-human primates, sponsored by the applicants, have shown that high dose weekly IV injections can lead to accumulation of drug in kidney proximal tubule cells. This accumulation resolved after termination of dosing, and there were no elevation of standard markers of kidney damage. However, dosing of DIVID patients will need to be life-long, and there has been no optimization of dosing schedules or drug concentrations that balance efficacy in muscle vs. kidney accumulation. Here, we bring together an interdisciplinary team to define the therapeutic window of morpholino dosing. Project 1 collaborates with an ongoing dose-ranging clinical trial to monitor kidney toxicity through urine biomarkers and shed renal cells. Project 2 defines the effects of AO concentrations, and dosing regimen on drug accumulation in kidney tubule cells, and also carries out a biomarker discovery program to define sensitive and reliable urine biomarkers for morpholino-associated cell damage. Project 3 defines the optimal dosing regimen able to provide sustained clinical efficacy in the mouse model of muscular dystrophy, using an established murine drug-testing core. A kidney toxicology assessment core supports these projects. PUBLIC HEALTH RELEVANCE: This project will provide clinical samples to monitor kidney accumulation of morpholino AO with chronic high dose IV treatment in boys with DMD. This project will integrate the pre-clinical and clinical data from the entire U54 program to derive inform optimized dosing and therapeutic index. The treatment of DMD using high dose IV morpholino is the most promising strategy for therapeutics of DMD. The possible consequences of long-term chronic treatment are not known. The data from this Project 2 will help define intervention targets and test tools for effective treatment of DMD using antisense morpholino. We will determine an optimized therapeutic window using the mouse efficacy and rat toxicity data above, including renal function tests, renal histology and ultrastructure, urine epithelial cel assays, and urine proteomic biomarker assays through Project 2 and Core B. Use of PMOs to correct genetic defects is rapidly advancing to several other human diseases such as FSHD, Cystic fibrosis, myotonic dystrophy, LGMD etc. Therefore, the data generated from this proposal have much broader implications than Duchenne muscular dystrophy.

描述（由申请人提供）：杜氏肌营养不良症是最常见的单基因儿科先天性缺陷，影响全世界每3,500名活产男性中的一名。DIVID最有希望的分子治疗方法是全身递送反义寡核苷酸（AO），其中药物改变mRNA剪接，并将框外丧失功能的转录物转化为能够产生半功能（贝克尔样）的框内转录物。 抗肌萎缩蛋白。在杜氏营养不良的大型动物（狗）模型中，我们已经表明静脉内（iV）递送高浓度的 剂量的吗啉代AO能够将抗肌萎缩蛋白的蛋白质产量挽救至野生型水平的约20%，并引起多个功能、组织学和成像结果测量的稳定或改善（Yokota等人，2009）。使用针对外显子51的吗啉代AO的初始人类临床试验已经表明，直接肌内注射和IV施用都可以导致肌营养不良蛋白的从头产生。然而，预计可能需要20 mg/kg - 100 mg/kg的重复剂量才能维持疗效。由申请人申办的小鼠和非人灵长类动物GLP毒性研究表明，高剂量每周IV注射可导致药物在肾近端小管细胞中蓄积。该蓄积在给药终止后消退，并且肾损伤的标准标志物未升高。然而，DIVID患者的给药将需要是终身的，并且尚未优化给药方案或药物浓度以平衡肌肉与肾脏累积的功效。在这里，我们汇集了一个跨学科的团队来定义吗啉给药的治疗窗口。项目1与正在进行的剂量范围临床试验合作，通过尿液生物标志物和脱落的肾细胞监测肾毒性。项目2定义了AO浓度和给药方案对药物在肾小管细胞中蓄积的影响，还进行了生物标志物发现计划，以定义吗啉相关细胞损伤的敏感和可靠的尿液生物标志物。项目3使用已建立的鼠药物测试核心，定义了能够在肌营养不良症小鼠模型中提供持续临床疗效的最佳给药方案。肾脏毒理学评估核心支持这些项目。 公共卫生关系：该项目将提供临床样本，以监测DMD男孩接受长期高剂量IV治疗后吗啉代AO的肾脏蓄积。该项目将整合整个U 54项目的临床前和临床数据，以获得最佳剂量和治疗指数。使用大剂量IV吗啉代治疗DMD是DMD治疗的最有前途的策略。长期慢性治疗的可能后果尚不清楚。来自该项目2的数据将有助于定义使用反义吗啉代有效治疗DMD的干预目标和测试工具。我们将使用上述小鼠疗效和大鼠毒性数据确定优化的治疗窗口，包括肾功能试验、肾组织学和超微结构、尿上皮细胞测定和尿蛋白质组生物标志物测定。 通过项目2和核心B。使用PMO纠正遗传缺陷正在迅速发展到其他几种人类疾病，如FSHD，囊性纤维化，强直性肌营养不良，LGMD等，因此，从这个建议产生的数据比杜氏肌营养不良症有更广泛的影响。