Charcot-Marie-Tooth disease type 1A (CMT1A), caused by a duplication in chromosome 17, results in peripheral myelin protein 22 (Pmp22) over-expression and axon demyelination. The diagnosis of CMT1A is based on decreased nerve conduction velocity (NCV) and compound muscle action potential (CMAP), with progressive muscle weakness and impaired sensations. Here, we provide a new therapy for CMT1A, based on the normalization of PMP22 expression by specific siRNA conjugated to squalene nanoparticles (siRNA PMP22-SQ NPs). Their administration resulted in the normalization of Pmp22 protein levels, reversed neuropathy scores and restored locomotor activity in two transgenic mouse models of CMT1A. Moreover, NCV and CMAP were significantly improved. Pathological studies demonstrated the regeneration of myelinated axons and myelin compaction. The normalization of sciatic nerve Krox20, Sox10 and neurofilament levels reflected the regeneration of both myelin and axons. Importantly, the positive effects of siRNA PMP22-SQ NPs lasted for as long as three weeks, and their renewed administration again resulted in full functional recovery. Beyond CMT1A, our findings can be considered as a potent therapeutic strategy for dominantly inherited peripheral neuropathies. They provide the proof of concept for a new precision therapy based on the normalization of disease gene expression by siRNA.
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