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是一种临床明显的疾病，其特征是眼外肌无力，周围神经病变， 引起严重恶病质、白质脑病和线粒体缺陷的胃肠动力障碍，包括 线粒体DNA异常(MtDNA)。这种疾病是无情的进行性和致命性的，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活性的严重丧失，从而显著提高组织和 血浆中胸腺嘧啶核苷(THD)和脱氧尿苷(DURD)的水平，这两种核苷可产生 脱氧核苷三磷酸(DNTP)库不平衡，进而导致线粒体DNA不稳定。基于 这些发现，我们假设TP酶通过异基因造血干细胞替代 移植(AHSCT)将通过消除有毒代谢物THD和DURD而具有治疗性，以及 正在恢复平衡的dNTP池。事实上，AHSCT的治疗效果得到了9个月的初步结果的支持 存活的、成功移植的MNGIE患者，他们的生化缺陷和 依赖时间的临床改进。不幸的是，在移植的第一阶段，在一系列 方案，生存不能接受(6/19，32%)。最初的结果在两个国际组织中进行了仔细的审查。 2008年和2010年在瑞士伯尔尼举行的会议，并导致制定了一项协商一致的议定书 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 NAMDC U54拨款申请，我们提出了一项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资助的前两年，NIH指定的数据安全 监测委员会(DSMB)提供了关键意见，导致将研究大幅重新设计为一个阶段 已经为其制定了方案的适应性安全性研究和研究人员新药(IND)应用 已初步获批。因此，我们现在建议检验假设AHSCT，在 MNGIE的共识方案可以安全地执行：1)移植后第42天移植物失败 (2)从预适应方案开始到移植后第100天的死亡率。此阶段1研究使用 高度创新的自适应安全停车规则设计，最大限度地减少了患者数量，同时 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.