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

线粒体神经胃肠脑肌病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。19年前，我们描述了 MNGIE是一种临床上独特的疾病，其特征在于眼外肌无力，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。这种疾病是无情的进步和致命的平均 发病年龄18岁，平均死亡年龄35岁。我们对MNGIE的研究 证明TYMP突变导致TP活性的严重丧失，从而显著升高组织和 嘧啶核苷胸苷（Thd）和脱氧尿苷（dUrd）的血浆水平， 脱氧核苷三磷酸（dNTP）池不平衡，这反过来又产生mtDNA的不稳定性。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， 通过消除毒性代谢物Thd和dUrd，AHSCT将是治疗性的， 恢复平衡的dNTP池。事实上，AHSCT的治疗效果得到了9项研究的初步结果的支持。 存活的、成功移植的MNGIE患者，这些患者已经显示出生化缺陷的纠正， 时间依赖性临床改善。不幸的是，在移植的第一阶段， 方案中，生存率不可接受（6/19，32%）。最初的结果在两个国际会议上得到了仔细的审查。 2008年和2010年在瑞士伯尔尼举行的会议上， 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。在初始 NAMDC U 54资助申请，我们提出了一项两阶段研究，从I期安全期开始 进入11期疗效研究。在U 54资助的前两年，NIH指定的数据安全 监查委员会（DSMB）提供了关键输入，导致研究重新设计为一个阶段 I适应性安全性研究，已编写方案并提交研究者新药（IND）申请 已初步批准。因此，我们现在提出测试假设，即AHSCT，在 MNGIE的共识方案，可以安全地进行1）移植后42天移植物衰竭 和2）预处理方案开始和移植后第100天之间的死亡率。这项1期研究使用了 高度创新的自适应安全停止规则设计，最大限度地减少了患者数量， 保持强大的力量来检验假设。

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.