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.

线粒体神经胃肠脑肌病（MNGIE）是一种罕见的常染色体隐性遗传病由编码胸苷磷酸化酶的 TYMP 基因突变引起。十九年前，我们描述过 MNGIE 是一种临床上独特的疾病，其特征是眼外肌无力、周围神经病变、胃肠动力障碍导致严重恶病质、白质脑病和线粒体缺陷，包括线粒体 DNA (mtDNA) 异常。这种疾病是无情地进展和致命的，平均发病年龄18岁，平均死亡年龄35岁。我们对 MNGIE 的研究有证明 TYMP 突变会导致 TP 活性严重丧失，从而显着提高组织和嘧啶核苷胸苷 (Thd) 和脱氧尿苷 (dUrd) 的血浆水平，产生脱氧核苷三磷酸 (dNTP) 库失衡，进而导致线粒体 DNA 不稳定。基于根据这些发现，我们假设通过同种异体造血干细胞替代 TP 酶移植（AHSCT）将通过消除有毒代谢物、Thd 和 dUrd 来起到治疗作用，并且恢复平衡的 dNTP 池。事实上，AHSCT 的治疗效果已得到 9 项初步结果的支持幸存、成功移植的 MNGIE 患者，其生化缺陷已得到纠正，并且依赖于时间的临床改善。不幸的是，在移植的第一阶段，在一系列的根据协议，生存率是不可接受的（6/19，32%）。初步结果经过两个国际组织的仔细审查 2008 年和 2010 年在瑞士伯尔尼举行的会议最终制定了一项共识协议最大限度地提高未来 AHSCT 的安全性。使用共识协议的初步结果是有希望的。在最初的 NAMDC U54 拨款申请，我们提出了从第一阶段安全期开始的两阶段研究过渡到 11 期疗效研究。在 U54 资助的前 2 年，NIH 指定的数据安全部门监测委员会 (DSMB) 提供了关键的意见，导致该研究进入一个阶段的实质性重新设计 I 适应性安全性研究，已为其编写方案并提交研究者新药 (IND) 申请已初步获批。因此，我们现在建议检验以下假设：AHSCT MNGIE 共识协议，可以安全地执行，因为 1) 移植后第 42 天移植失败 2) 预处理方案开始至移植后 100 天之间的死亡率。该第一阶段研究使用高度创新的自适应安全停止规则设计，最大限度地减少患者数量，同时保持强大的力量来检验假设。