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.

Pharmacogenetic Discovery in CALGB (Alliance) 90401 and Mechanistic Validation of a VAC14 Polymorphism that Increases Risk of Docetaxel-Induced Neuropathy

“…In the larger DGN cohort (n=922), rs875858 is highly associated with IL34 (p=4e-7) expression in whole blood. IL-34 is structurally similar to colony-stimulating factor 1 and both are ligands of the colony-stimulating factor 1 receptor(43), which has recently been identified as an efficacious target in mouse models of Charcot-Marie-Tooth disease(44), providing an alternative plausible biological mechanism for this association. Finally, it is conceivable that this SNP is not functionally relevant but instead is a genetic marker of a different causative SNP; however, rs875858 lies in a region of low linkage disequilibrium.…”

Recent advances in the genetic neuropathies

“…In a mouse model of CMT1X (GJB1 null), treatment with a CSF-1 receptor antagonist was able to reduce the number of endoneurial macrophages leading to improved grip strength and compound muscle action potentials (CMAPs) of distal muscles [28**]. The same effect was demonstrated in a CMT1B, but not a CMT1A, mouse model (although a similar reduction in endoneurial macrophages was seen in the CMT1A model).…”

Inflammation in Alzheimer’s disease: Lessons learned from microglia-depletion models

“…The transient impairment in cognitive function is presumably due to behavioral assessment occurring at a time point in which microglia are still in the process of dying. Importantly, multiple groups have utilized PLX3397, as well as the CSF1R-specific inhibitor PLX5622 to eliminate microglia (De et al, 2014; Valdearcos et al, 2014; Asai et al, 2015; Klein et al, 2015; Schreiner et al, 2015), without inducing adverse effects on cognitive function in adult mice (Dagher et al, 2015; Rice et al, 2015; Spangenberg et al, 2016). …”