Antisense Oligonucleotides Targeting PMP22 Show Promise for the Treatment of Charcot-Marie-Tooth Disease

Suppression of PMP22 with Antisense Oligonucleotides Reverses Features of CMT1A in Preclinical Models

Data Published in The Journal of Clinical Investigations

Ionis scientists and collaborators evaluated the effects of suppressing peripheral myelin protein 22 (PMP22) mRNA with antisense oligonucleotides in two rodent models of Charcot-Marie-Tooth disease type 1 A (CMT1A). Investigators also assessed the viability of measuring PMP22 mRNA by skin biopsy as a suitable biomarker to evaluate overall target engagement. Key preclinical findings were recently published in The Journal of Clinical Investigations in a paper titled, “PMP22 antisense oligonucleotides reverse clinical, pathological, and molecular features of Charcot-Marie-Tooth disease type 1A.”

“We are thrilled to support Ionis in the development of PMP22-targeting antisense drugs. The preclinical findings published in The Journal of Clinical Investigations are an important step towards understanding PMP22 and its role in CMT1A,” said Amy Gray, CEO of the Charcot-Marie-Tooth Association. “Using antisense to target PMP22 offers an exciting therapeutic opportunity for CMT1A patients who currently do not have available treatment options.”

Charcot-Marie-Tooth disease (CMT) is the most common hereditary disease affecting the peripheral nerves. Symptoms include weakness of the foot and lower leg muscles, resulting in frequent tripping or falls, structural foot deformities, muscle wasting and atrophy in lower legs and hands.1 While CMT is not fatal, this disease can be severely disabling and currently, there are no available therapies for these patients.

CMT1A, the most prevalent form of CMT, is inherited in an autosomal dominant manner. CMT1A is caused by duplication of the PMP22 gene on Chromosome 17, resulting in three copies of the gene instead of two. Pathologically, CMT1A is characterized by demyelination and axonal loss, which underlie the slowed motor nerve conduction velocity (MNCV) and reduced compound muscle action potentials (CMAP) in patients. PMP22 is a structural protein in the Schwann cell myelin sheath, and too much PMP22 results in demyelination. Previous studies in rodent models verified that overexpression of PMP22 results in demyelinating neuropathy, while subsequent reduction of once overexpressed PMP22 led to remyelination.2 Because elevated levels of PMP22 can be measured in the dermal and sural nerves of patients with CMT1A, PMP22 can potentially be used as a biomarker to evaluate target engagement. Although reducing PMP22 is an attractive approach for the treatment of CMT1A, no other therapeutic modality has been able to directly effect this target.

Investigators demonstrated that subcutaneous, systemic delivery of PMP22-targeting antisense oligonucleotides (ASOs) dose-dependently suppress PMP22 mRNA in affected nerves in two animal models of CMT1A. Notably, treatment initiated post disease onset restored the structure and function of myelinated axons in treated animals to nearly wildtype levels – improving myelination by histological analysis of nerves, as well as normalizing the amplitude and the velocity of peripheral nerve conduction. Through transcriptomic profiling, investigators also identified gene expression networks that were altered in disease and restored with ASO treatment, as well as novel disease biomarkers that can be used in clinical trials. These results suggest that PMP22 could serve as a useful biomarker of target engagement for this indication.

These preclinical results validate PMP22 as a therapeutic target for CMT1A and highlight the therapeutic utility of antisense-mediated suppression of PMP22 as a promising approach to treat this severe disease. Notably, these results mark the first program to show benefit in animal models of CMT disease. Ionis, with the support of Charcot-Marie-Tooth Association (CMTA) USA, will continue to evaluate PMP22-targeting antisense drugs to identify an optimal drug candidate to advance into clinical development to treat patients with CMT1A.


  1. Zhao et al., “PMP22 antisense oligonucleotides reverse clinical, pathological, and molecular features of Charcot-Marie-Tooth disease type 1A.” The Journal of Clinical Investigations, Advanced Online Publication, December 4, 2017. (link:
  2. Perea, J., et al., Induced myelination and demyelination in a conditional mouse model of Charcot-Marie-Tooth disease type 1A. Hum Mol Genet, 2001. 10(10): p. 1007-18.