Molecular pathogenesis and Treatment of MNGIE.

Following the models constructed of novel polymeric nanoparticles encapsulating human thymidine phosphorylase for which in vitro studies indicate that the TP-nanoreactors are enzymatically active and stable in blood. We will continue to perform pharmcokinetic studies to establish the tissue distribution and half-life of TPNR, followed by short-term toxicity and pharmacokinetic studies by administering TP-NR long-term to nucleoside-stressed TP/UP/mice to assess efficacy. We will use neuroimaging biomarkers to non-invasively monitor mice serially for leukoencephalopathy by T2-weighted MRI and for metabolic dysfunction by MRS scans. We will monitor mice for signs of distress, clinical manifestations related to thymidine phosphorylase deficiency, and complications related to TP-NR toxicity. ERT is a promising alternative to alloSCT. In addition to the neuroradiological evaluations, clinical assessments of the TP/UP/mice will be performed for signs of gastrointestinal dysmotility, cachexia, peripheral neuropathy, myopathy, and ptosis that are the hallmark features of MNGIE.