title: Targeting the colony stimulating factor 1 receptor alleviates two forms of Charcot-Marie-Tooth disease in mice.
abstract: See Scherer (doi:10.1093/awv279) for a scientific commentary on this article.Charcot-Marie-Tooth type 1 neuropathies are inherited disorders of the peripheral nervous system caused by mutations in Schwann cell-related genes. Typically, no causative cure is presently available. Previous preclinical data of our group highlight the low grade, secondary inflammation common to distinct Charcot-Marie-Tooth type 1 neuropathies as a disease amplifier. In the current study, we have tested one of several available clinical agents targeting macrophages through its inhibition of the colony stimulating factor 1 receptor (CSF1R). We here show that in two distinct mouse models of Charcot-Marie-Tooth type 1 neuropathies, the systemic short- and long-term inhibition of CSF1R by oral administration leads to a robust decline in nerve macrophage numbers by ∼70% and substantial reduction of the typical histopathological and functional alterations. Interestingly, in a model for the dominant X-linked form of Charcot-Marie-Tooth type 1 neuropathy, the second most common form of the inherited neuropathies, macrophage ablation favours maintenance of axonal integrity and axonal resprouting, leading to preserved muscle innervation, increased muscle action potential amplitudes and muscle strengths in the range of wild-type mice. In another model mimicking a mild, demyelination-related Charcot-Marie-Tooth type 1 neuropathy caused by reduced P0 (MPZ) gene dosage, macrophage blockade causes an improved preservation of myelin, increased muscle action potential amplitudes, improved nerve conduction velocities and ameliorated muscle strength. These observations suggest that disease-amplifying macrophages can produce multiple adverse effects in the affected nerves which likely funnel down to common clinical features. Surprisingly, treatment of mouse models mimicking Charcot-Marie-Tooth type 1A neuropathy also caused macrophage blockade, but did not result in neuropathic or clinical improvements, most likely due to the late start of treatment of this early onset disease model. In summary, our study shows that targeting peripheral nerve macrophages by an orally administered inhibitor of CSF1R may offer a highly efficacious and safe treatment option for at least two distinct forms of the presently non-treatable Charcot-Marie-Tooth type 1 neuropathies.
authors: 1 Department of Neurology, Developmental Neurobiology, University Hospital Würzburg Josef-Schneider Str. 11, D-97080 Würzburg, Germany.
authors: Dennis
authors: D
authors: Klein
authors: 1 Department of Neurology, Developmental Neurobiology, University Hospital Würzburg Josef-Schneider Str. 11, D-97080 Würzburg, Germany.
authors: Ágnes
authors: Á
authors: Patzkó
authors: 1 Department of Neurology, Developmental Neurobiology, University Hospital Würzburg Josef-Schneider Str. 11, D-97080 Würzburg, Germany.
authors: David
authors: D
authors: Schreiber
authors: 1 Department of Neurology, Developmental Neurobiology, University Hospital Würzburg Josef-Schneider Str. 11, D-97080 Würzburg, Germany.
authors: Anemoon
authors: A
authors: van Hauwermeiren
authors: 1 Department of Neurology, Developmental Neurobiology, University Hospital Würzburg Josef-Schneider Str. 11, D-97080 Würzburg, Germany.
authors: Michaela
authors: M
authors: Baier
authors: 1 Department of Neurology, Developmental Neurobiology, University Hospital Würzburg Josef-Schneider Str. 11, D-97080 Würzburg, Germany.
authors: Janos
authors: J
authors: Groh
authors: 2 Plexxikon Inc., Berkeley CA 94710, USA.
authors: Brian L
authors: BL
authors: West
authors: 1 Department of Neurology, Developmental Neurobiology, University Hospital Würzburg Josef-Schneider Str. 11, D-97080 Würzburg, Germany rudolf.martini@uni-wuerzburg.de.
authors: Rudolf
authors: R
authors: Martini
mesh_terms: D000818:Animals; D001369:Axons / Q000187:drug effects* / Q000473:pathology; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D017630:Connexins / Q000172:deficiency / Q000235:genetics; D003711:Demyelinating Diseases / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D018737:Hand Strength; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D018993:Myelin P0 Protein / Q000235:genetics; D009185:Myelin Proteins / Q000235:genetics; D009431:Neural Conduction / Q000187:drug effects*; D010525:Peripheral Nerves / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors* / Q000276:immunology; D000097002:Gap Junction beta-1 Protein
chemical_list: D017630:Connexins; D018993:Myelin P0 Protein; D009185:Myelin Proteins; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D000097002:Gap Junction beta-1 Protein; C000604004:Csf1r protein, mouse; C560546:Mpz protein, mouse; C489545:Pmp22 protein, mouse
keywords: Schwann cell; inherited neuropathy; macrophage; myelin; neuroinflammation