The mucopolysaccharidoses (MPS) are rare genetic disorders marked by severe somatic and neurological symptoms. Development of treatments for the neurological manifestations of MPS has been hindered by the lack of objective measures of central nervous system disease burden. Identification of biomarkers for central nervous system disease in MPS patients would facilitate the evaluation of new agents in clinical trials. High throughput metabolite screening of cerebrospinal fluid (CSF) samples from a canine model of MPS I revealed a marked elevation of the polyamine, spermine, in affected animals, and gene therapy studies demonstrated that reduction of CSF spermine reflects correction of brain lesions in these animals. In humans, CSF spermine was elevated in neuropathic subtypes of MPS (MPS I, II, IIIA, IIIB), but not in subtypes in which cognitive function is preserved (MPS IVA, VI). In MPS I patients, elevated CSF spermine was restricted to patients with genotypes associated with CNS disease and was reduced following hematopoietic stem cell transplantation, which is the only therapy currently capable of improving cognitive outcomes. Additional studies in cultured neurons from MPS I mice showed that elevated spermine was essential for the abnormal neurite overgrowth exhibited by MPS neurons. These findings offer new insights into the pathogenesis of CNS disease in MPS patients, and support the use of spermine as a new biomarker to facilitate the development of next generation therapeutics for MPS.
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We would like to acknowledge Margaret Maronski and the Neuron Culture Services Core (Mahoney Institute of Neurological Sciences, Perelman School of Medicine, University of Pennsylvania) for assistance with neuron isolation and culture. We would like to thank Marc A. Dichter (Mahoney Institute of Neurological Sciences, Perelman School of Medicine, University of Pennsylvania) for providing expertise on neuron culture and morphometric studies. We would like to thank Mark Haskins, Patty O'Donnell, and Jessica Bagel for providing canine CSF samples. We would also like to acknowledge the support of the Morphology Core (Gene Therapy Program, Perelman School of Medicine, University of Pennsylvania). We also thank Jennifer Stewart for editorial assistance with this manuscript. This work was supported by the National Institute of Environmental Health Sciences of the National Institutes of Health under award number P30ES013508, and by the Orphan Disease Center at the University of Pennsylvania.
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