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

基本信息

批准号：
8472511
负责人：
JOHANNES NICOLAAS VAN DEN ANKER
金额：
$ 76.66万
依托单位：
CHILDREN'S RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
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/8472511
关键词：
Affect Antisense Oligonucleotides Area Awareness Biological Assay Biological Markers Canis familiaris Cells Chemistry Childhood Chronic Clinical Clinical Data Clinical Trials Community Health Education Community Outreach Cystic Fibrosis Data Development Disease Dose Duchenne muscular dystrophy Dystrophin Epithelial Equilibrium Exons General Population Goals Histology Home environment Human Image Inborn Genetic Diseases Injection of therapeutic agent Intervention Intramuscular Injections Intravenous Kidney Lead Life Messenger RNA Modeling Molecular Monitor Monkeys Mus Muscle Mutation Myotonic Dystrophy Outcome Measure Patients Pharmaceutical Preparations Pharmacology Production Proteins Proteomics Proximal Kidney Tubules Quality of life RNA Splicing Rattus Regimen Renal function Renal tubule structure Research Research Activity Research Personnel Resolution Resources Sampling Schedule Scientist Specialized Center Testing Therapeutic Therapeutic Index Toxic effect Toxicology Training Transcript Translating Translational Research Urine base boys career career development cell injury clinical efficacy drug testing effective therapy exon skipping expectation human disease improved in vivo interest kidney cell loss of function male multidisciplinary muscular dystrophy mouse model nonhuman primate pediatric pharmacology pre-clinical preclinical study programs tool treatment effect

项目摘要

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.

描述（由申请人提供）：Duchenne肌肉营养不良症是最常见的单基因天生误差，全世界影响了3500名活出生的男性。除分裂的最有前途的分子治疗方法是全身递送抗敏感性寡核苷酸（AOS），其中药物会改变mRNA剪接，并转化掉框架外损失函数转录本，以产生能够产生半功能（Becker样）（Becker样）的框架内转录本肌营养不良。在Duchenne营养不良的大型动画（Dog）模型中，我们已经表明了静脉（IV）高高的递送剂量的morpholino AOS能够将产生肌营养不良蛋白的产生至约20％的野生型水平，并导致多种功能，组织学和成像结果指标的稳定或改善（Yokota等，2009）。最初使用针对外显子51的Morpholino AO进行的人类临床试验表明，直接肌内注射和IV施用都可以导致从头肌营养不良蛋白的产生。但是，预计重复剂量为20 mg/kg -100 mg/kg可能需要持续功效。由申请人赞助的小鼠和非人类灵长类动物的GLP毒性研究表明，高剂量的每周IV注射可以导致药物在肾脏近端小管细胞中的积累。终止给药后解决了这种积累，肾脏损伤的标准标记没有升高。但是，分裂患者的剂量将需要终身，并且没有优化给药时间表或药物浓度，这平衡了肌肉与肾脏积累的疗效。在这里，我们将一个跨学科的团队召集在一起，以定义Morpholino剂量的治疗窗口。项目1与持续的剂量临床试验合作，通过尿液生物标志物和肾细胞监测肾脏毒性。项目2定义了AO浓度的作用，并给药方案对肾小管细胞中药物的积累的影响，并执行生物标志物发现程序，以定义敏感可靠的尿液生物标志物，以实现莫菲利诺相关的细胞损伤。项目3定义了最佳的剂量方案，能够使用已建立的鼠类药物测试核心在肌肉营养不良的小鼠模型中提供持续的临床功效。肾脏毒理学评估核心支持这些项目。