Presymptomatic macrophage targeting has a long-lasting therapeutic effect on treatment termination in a mouse model of Charcot-Marie-Tooth 1

Abstract

Macrophage-mediated inflammation is a potent driver of disease progression in mouse models of Charcot-Marie-Tooth (CMT) 1 diseases. This leads to the possibility to consider these cells as therapeutic targets to dampen disease outcome in the so far non-treatable neuropathies. As a pharmacological proof-of-principle study, long-term targeting of nerve macrophages with the orally applied CSF-1 receptor specific kinase (c-FMS) inhibitor PLX5622 showed a substantial alleviation of the neuropathy in distinct CMT1 mouse models. However, regarding translational options, clinically relevant questions emerged regarding treatment onset, duration and termination.Corroborating previous data, we here show that in a model for CMT1B, peripheral neuropathy was substantially alleviated after early continuous PLX5622 treatment in CMT1B mice, leading to preserved motor function. However, late-onset treatment failed to mitigate histopathological and clinical features, despite a similar reduction in the number of macrophages. Surprisingly, in CMT1B mice, terminating early PLX5622 treatment at six months was still sufficient to preserve motor function at 12 months of age, suggesting a long-lasting, therapeutic effect of early macrophage depletion. This novel and unexpected finding may have important translational implications, since we here show that continuous macrophage targeting appears not to be necessary for disease alleviation, provided that the treatment starts within an early, critical time window.