Will new investigational drugs change the way we treat Charcot-Marie-Tooth disease?

Figures & data

Figure 1. Schematic representation of a motor neuron with its myelinated axon, neuromuscular junction and innervated muscle fiber. A transversal section of an internode with the myelinating Schwann cell is also shown. A list of potential treatments already tested, under evaluation, or under development is provided for each CMT type or related protein. [with permission from ‘Pisciotta C, Pareyson D. Gene therapy and other novel treatment approaches for Charcot-Marie-tooth disease. Neuromuscul Disord. 2023;33(8):627–635. doi:https://10.1016/j.Nmd.2023.07.001E28099’].

Table 1. PMP22 gene silencing approaches for treating CMT1A in animal models.

Approach	Method and route of administration	Animal model	Comment	Reference
ASO	Repeated subcutaneous injections	C22 mice, CMT1A rats	Need for repeated administration	[4]
Squalenoyl siRNA nanoparticles	Repeated intravenous injections	JP18 and JP18/JY13 mice	Need for repeated administration	[5]
Fatty-acid-siRNA conjugated	Repeated intravenous injections	C3 mice	Need for repeated administration	[6]
AAV2/9 shRNA	Single intraneural injection	CMT1A rats	Multiple sites of injection required; risk of nerve damage	[7]
LV-miRNA (miR-381)	Single intraneural injection	C22 mice	Risks associated with lentiviral vectors; risk of nerve damage	[8]
scAAV9 miRNA (miR-871)	Single lumbar intrathecal injection	C61 mice	Greater diffusion ability than by intraneural administration	[9]
CRISPR/Cas9 liposomal PMP22 TATA box RNP-mediated editing	Single intraneural injection	C22 mice	Risk of nerve damage	[10]
CRISPR/Cas9 PMP22 TATA box AAV-mediated editing	Single intravenous or intratechal injection	C22 and C3 mice, CMT1A rats	Greater efficacy in intravenous compared to intratechal administration	[11]

Efficacy demonstrated on behavioral, electrophysiological, and histological level for the majority of the approaches (only for the CRISPR/Cas9 approach no data on behavioral effects are reported). General remarks: need to target a sufficient number of Schwann cells avoiding at the same time potential unwanted off-target effects; risk of HNPP if excessive downregulation.

Abbreviations: AAV=adeno-associated viral (vector); ASO=antisense oligonucleotides; CRISPR/Cas9=clustered regularly interspaced short palindromic repeats/associated protein 9; HNPP=hereditary neuropathy with liability to pressure palsies; LV=lentiviral (vector); miRNA=microRNA; RNP=ribonucleoprotein; shRNA=short hairpin RNA; siRNA=short interfering RNA.

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Lee J-S, Kwak G, Kim HJ, et al. miR-381 attenuates peripheral neuropathic phenotype caused by overexpression of PMP22. Exp Neurobiol. 2019;28(2):279–288. doi: 10.5607/en.2019.28.2.279

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Stavrou M, Kagiava A, Choudury SG, et al. A translatable RNAi-driven gene therapy silences PMP22/Pmp22 genes and improves neuropathy in CMT1A mice. J Clin Invest. 2022;132(13):e159814. doi: 10.1172/JCI159814

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