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

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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.