Editors' ChoiceNeurological Disease

Two Paths Diverged in a Schwann Cell

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Science Translational Medicine  10 Sep 2014:
Vol. 6, Issue 253, pp. 253ec157
DOI: 10.1126/scitranslmed.3010405

Aberrations in the genetic code are the underlying cause of countless human diseases. Whereas advances in genome sequencing technologies and genetic screening now enable rapid and accurate molecular diagnoses, there still exist major challenges to the treatment of most genetic diseases. In the absence of gene therapy, treatment involves managing symptoms rather than improving or restoring function. Using cellular and animal models of a common neurogenetic disease, Charcot-Marie-Tooth 1A, Fledrich et al. now show that precise temporal and cell type–specific modulation of aberrant signaling pathways is a new therapeutic strategy for treating this disease.

Charcot-Marie-Tooth 1A is an inherited peripheral neuropathy caused by duplication of a region on chromosome 17, which includes the PMP22 gene. Patients typically present as young adults with sensory and motor deficits caused by peripheral demyelination and subsequent neuronal loss. Current therapies are palliative, largely owing to a limited understanding of molecular mechanisms by which PMP22 duplication leads to disease. In the current study, the authors use rodent models of Charcot-Marie-Tooth 1A to uncover an intracellular signaling imbalance between the PI3K-Akt and Mek-Erk signaling pathways in early postnatal Schwann cells. Specifically, Charcot-Marie-Tooth 1A mutant Schwann cells exhibited a persistent defect in their ability to differentiate into myelinating Schwann cells, which correlated with increased Mek-Erk signaling and decreased PI3K-Akt activity. In a substantial translational advance, they tested whether modulation of this signaling imbalance by extrinsic cues could restore mutant Schwann cell differentiation and myelination. Intraperitoneal injections of recombinant human neuregulin-1 protein into Charcot-Marie-Tooth 1A mice during postnatal days 6 to 18 enhanced PI3K-Akt activity in mutant Schwann cells, restored the number of myelinated axons to that of wild-type animals, and improved motor function into adulthood.

Whereas genome-editing technologies provide promise for a subset of genetic disorders, cures for the remainder will rely heavily on a precise understanding of the temporal and cell type–specific molecular aberrations driving the disease. As in the current study, assays including model organisms as well as induced pluripotent stem cells will continue to enable the ability of researchers to accurately define such aberrations and test lead therapeutic interventions. Given that recombinant human neuregulin-1 protein has already been proven safe in clinical trials for heart diseases, it is likely that it could be rapidly tested in clinical trials for patients with Charcot-Marie-Tooth 1A . However, such trials may prove challenging to evaluate, given that treatment would need to be administered to presymptomatic children and that therapeutic efficacy could not be evaluated until adulthood.

R. Fledrich et al., Soluble neuregulin-1 modulates disease pathogenesis in rodent models of Charcot-Marie-Tooth disease 1A. Nat. Med. 10.1038/nm.3664 (2014). [Full Text]

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