Abstract
Charcot-Marie-Tooth disease type 1 A (CMT1A) lacks an effective treatment. We provide a therapy for CMT1A, based on siRNA conjugated to squalene nanoparticles (siRNA PMP22-SQ NPs). Their administration resulted in normalization of Pmp22 protein levels, restored locomotor activity and electrophysiological parameters in two transgenic CMT1A mouse models with different severity of the disease. Pathological studies demonstrated the regeneration of myelinated axons and myelin compaction, one major step in restoring function of myelin sheaths. 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 three weeks, and their renewed administration resulted in full functional recovery. Beyond CMT1A, our findings can be considered as a potent therapeutic strategy for inherited peripheral neuropathies. They provide the proof of concept for a new precision medicine based on the normalization of disease gene expression by siRNA.
Highlights
Charcot-Marie-Tooth disease type 1 A (CMT1A) lacks an effective treatment
An optimal siRNA candidate should inhibit between 30 and 50% of PMP22 expression and restore normal levels of Pmp[22] protein, which are increased by 1.5- to 2-folds in CMT1A patients as mention by Svaren et al.[26]
We selected the optimal concentration of siPMP7 (50 nM) that showed no significant effect on P0 and on cell viability, and this condition was used for further experiments and is referred to as siRNA PMP22 for the rest of the study (Supplementary Fig. 2e)
Summary
We provide a therapy for CMT1A, based on siRNA conjugated to squalene nanoparticles (siRNA PMP22SQ NPs) Their administration resulted in normalization of Pmp[22] protein levels, restored locomotor activity and electrophysiological parameters in two transgenic CMT1A mouse models with different severity of the disease. Genetic therapy was introduced by Zhao et al by using antisense oligonucleotides (ASO) in CMT1A animal models and showed promising results[14] Due to their mechanism of action, siRNA offer important advantages, in particular their high degree of safety as they inhibit gene expression at a posttranslational level and do not directly interact with DNA, their high efficacy in suppressing gene expression and their specificity determined by complementary base pairing[15]
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