Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive disease caused by mutations in the TYMP gene encoding thymidine phosphorylase. Seventeen 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 19-years-old and an average age-at-death of 37-years-old. We have mapped the disease locus to chromosome 22q13.32-tel, identified the causative gene, characterized the molecular pathogenesis, and generated a mouse model. 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 10 surviving, successfully transplanted MNGIE patients who have shown restoration of circulating TP activity, marked reductions of the toxic metabolites, Thd and dUrd, and time-dependent clinical improvements. In the first phase of transplants, under a range of protocols, survival was unacceptable (7/14, 50%), However, the initial results were carefully reviewed in two international meetings held in Bern, Switzerland in November, 2008 and February, 2010. A revised consensus protocol to maximize safety in future AHSCT was developed and published. Initial survival results under it are acceptable to date. We therefore propose here to evaluate AHSCT for MNGIE through a confirmatory safety study followed by a phase ll randomized clinical trial (RCT) comparing biomarker outcome in transplanted to untransplanted patients.
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