Rare Dis Clin Res Consortia (RDCRC) for Rare Dis Clin Res Network (U54)

罕见疾病临床研究联盟 (RDCRC) 的罕见疾病临床研究网络 (U54)

基本信息

批准号：
9145796
负责人：
MICHIO HIRANO
金额：
$ 29.43万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9145796
关键词：
18 year old 19 year old Age Allogeneic Bone Marrow Transplantation Allogenic American Applications Grants Biochemical Biological Biometry Cachexia Cause of Death Cessation of life Chromosomes Clinical Clinical Trials Data Monitoring Committees Computers Consensus Data Defect Deoxyuridine Development Disease Enzymes Equilibrium Ethnic group Funding Future Genes Grant Hematologist Hematopoietic stem cells Hereditary Disease Instruction International Leukoencephalopathy Maps Measures Mitochondria Mitochondrial DNA Mitochondrial Diseases Mitochondrial Encephalomyopathies Molecular Muscle Weakness Mutation Neurologist Online Mendelian Inheritance In Man Online Systems Ophthalmoplegia Outcome Outcome Measure Pathogenesis Patients Peripheral Nervous System Diseases Phase Plasma Point Mutation Prevalence Protocols documentation Ptosis Publishing Pyrimidine Nucleosides Recommendation Regimen Research Research Design Research Personnel Resources Safety Secure Site Skeletal Muscle Statistical Data Interpretation Stem cell transplant Switzerland Teenagers Testing Therapeutic Thymidine Thymidine Phosphorylase Time Tissues Transplantation Treatment Efficacy United States National Institutes of Health Universities Work Writing base conditioning data management design disease-causing mutation experience gastrointestinal graft failure improved innovation meetings mortality motility disorder mouse model novel therapeutics orbit muscle phase 1 study restoration safety study safety testing trial design tripolyphosphate

项目摘要

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive disease caused by mutations in the TYMP gene encoding thymidine phosphorylase. Nineteen years ago, we described MNGIE as a clinically distinct disorder characterized by extraocular muscle weakness, peripheral neuropathy, gastrointestinal dysmotility causing severe cachexia, leukoencephalopathy, and mitochondrial defects including abnormalities of mitochondrial DNA (mtDNA). The disease is relentlessly progressive and fatal with an average age-at-onset of 18-years-old and an average age-at-death of 35-years-old. Our studies of MNGIE have demonstrated that TYMP mutations cause severe loss of TP activity that dramatically elevates tissue and plasma levels of the pyrimidine nucleosides thymidine (Thd) and deoxyuridine (dUrd), which produce deoxynucleoside triphosphate (dNTP) pool imbalances that, in turn, produce instability of mtDNA. Based on these findings, we have hypothesized that TP enzyme replacement via allogeneic hematopoetic stem cell transplantation (AHSCT) will be therapeutic by virtue of eliminating the toxic metabolites, Thd and dUrd, and restoring balanced dNTP pools. In fact, therapeutic efficacy of AHSCT is supported by preliminary results in 9 surviving, successfully transplanted MNGIE patients who have shown corrections of biochemical defects and time-dependent clinical improvements. Unfortunately, in the first phase of transplants, under a range of protocols, survival was unacceptable (6/19, 32%). The initial results were carefully reviewed in two international meetings held in Bern, Switzerland in 2008 and 2010 and led to development of a consensus protocol to maximize safety in future AHSCTs. Preliminary results using the consensus protocol are promising. In the initial NAMDC U54 grant application, we proposed a two-phase study beginning with a phase I safety period transitioning into a phase 11 efficacy study. In the first 2 years of U54 funding, a NIH-appointed Data Safety Monitoring Board (DSMB) has provided critical input leading to a substantial redesign of the study into a phase I adaptive safety study for which a protocol has been written and an Investigator New Drug (IND) application has been preliminarily approved. Thus, we now propose to test the hypothesis that AHSCT, under the consensus protocol for MNGIE, can be performed safely in terms of 1) graft failure at day 42 post-transplant and 2) mortality between conditioning regimen initiation and day 100 post-transplant. This Phase 1 study uses a highly innovative adaptive safety stopping rule design, which minimizes the number of patients while maintaining robust power to test the hypothesis.

线粒体神经胃肠道脑病（MNGIE）是一种罕见的常染色体隐性疾病由编码胸苷磷酸化酶的TYMP基因突变引起的。十九年前，我们描述了 mngie是一种临床上不同的疾病，其特征是眼外肌肉无力，周围神经病，胃肠道不良运动引起严重的恶病质，白血病和线粒体缺陷，包括线粒体DNA（mtDNA）的异常。这种疾病是无情的，致命的，平均 18岁的年龄和年龄为35岁的平均年龄。我们对Mngie的研究表明TYMP突变会导致TP活性严重丧失，从而显着提升组织和嘧啶核苷胸苷（THD）和脱氧尿苷（DURD）的血浆水平，它们产生脱氧核苷三磷酸（DNTP）池不平衡，而磁磷酸盐不平衡会产生mtDNA的不稳定性。基于这些发现，我们假设TP酶通过同种异体造血干细胞替换通过消除有毒代谢物，THD和DURD，移植（AHSCT）将具有治疗性恢复平衡的DNTP池。实际上，在9 幸存的，成功移植的MNGIE患者，他们显示了生化缺陷的校正和时间依赖性临床改进。不幸的是，在移植的第一阶段，方案，生存是不可接受的（6/19，32％）。在两个国际 2008年和2010年在瑞士伯尔尼举行的会议，并制定了共识协议最大化未来AHSCT的安全性。使用共识协议的初步结果是有希望的。在最初 NAMDC U54赠款应用程序，我们提出了一项从I期安全期开始的两阶段研究过渡到11期疗效研究。在U54资金的前两年，NIH任命的数据安全监测委员会（DSMB）提供了关键的输入，从而将研究重新设计为一个阶段我适应已经编写了协议的安全性研究，并应用了调查员新药（IND）已获得初步批准。因此，我们现在建议检验AHSCT的假设 MNGIE的共识协议可以安全执行1）移植后第42天的移植失败 2）调节方案开始与移植后第100天之间的死亡率。该阶段1研究使用高度创新的自适应安全性停止规则设计，这使患者数量最小保持强大的能力检验假设。