PMP22 antisense oligonucleotides reverse Charcot-Marie-Tooth disease type 1A features in rodent models
Hien Tran Zhao, … , Eric E. Swayze, Holly B. Kordasiewicz
Hien Tran Zhao, … , Eric E. Swayze, Holly B. Kordasiewicz
Published January 2, 2018; First published December 4, 2017
Citation Information: J Clin Invest. 2018;128(1):359-368. https://doi.org/10.1172/JCI96499.
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Research Article Neuroscience Therapeutics

PMP22 antisense oligonucleotides reverse Charcot-Marie-Tooth disease type 1A features in rodent models

Abstract

Charcot-Marie-Tooth disease type 1A (CMT1A) is caused by duplication of peripheral myelin protein 22 (PMP22) and is the most common hereditary peripheral neuropathy. CMT1A is characterized by demyelination and axonal loss, which underlie slowed motor nerve conduction velocity (MNCV) and reduced compound muscle action potentials (CMAP) in patients. There is currently no known treatment for this disease. Here, we show that antisense oligonucleotides (ASOs) effectively suppress PMP22 mRNA in affected nerves in 2 murine CMT1A models. Notably, initiation of ASO treatment after disease onset restored myelination, MNCV, and CMAP almost to levels seen in WT animals. In addition to disease-associated gene expression networks that were restored with ASO treatment, we also identified potential disease biomarkers through transcriptomic profiling. Furthermore, we demonstrated that reduction of PMP22 mRNA in skin biopsies from ASO-treated rats is a suitable biomarker for evaluating target engagement in response to ASO therapy. These results support the use of ASOs as a potential treatment for CMT1A and elucidate potential disease and target engagement biomarkers for use in future clinical trials.

Authors

Hien Tran Zhao, Sagar Damle, Karli Ikeda-Lee, Steven Kuntz, Jian Li, Apoorva Mohan, Aneeza Kim, Gene Hung, Mark A. Scheideler, Steven S. Scherer, John Svaren, Eric E. Swayze, Holly B. Kordasiewicz

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Figure 1

Behavioral, electrophysiological, and pathological improvement after ASO treatment in C22 model.

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Behavioral, electrophysiological, and pathological improvement after ASO...
Five-week-old C22 mice were treated with weekly subcutaneous injections of PB, control ASO (CTRL; 50 mg/kg), or ASO1 at 25, 50, or 100 mg/kg per week for 9 weeks. n = 8 per group. WT littermates treated with PBS were included as controls. n = 8. CTRL, control. (A and B) Human PMP22 and mouse Pmp22 mRNA levels in sciatic nerves of treated mice. One-way ANOVA with Dunnett’s post test. *P < 0.05; **P < 0.01; ***P < 0.001. (C) The hind limb grip strength (g) and (D) time remaining on rotarod (s) were measured before treatment began (pretreatment) and at 3, 6, and 9 weeks following treatment. Two-way ANOVA with Tukey’s post test was used to compare pretreated C22 vs. WT (#P < 0.05) or pretreated and posttreated disease groups. *P < 0.05; **P < 0.01; ***P < 0.001. (E) MNCV was measured at pretreatment and at 9 weeks following treatment. Two-way ANOVA with Tukey’s post test was used to compare pretreated C22 versus WT (#P < 0.05) or pretreated and posttreated disease groups. ***P < 0.001. (F) CMAP was measured at 9 weeks after treatment. ASO1-treated groups were compared with PBS group using 1-way ANOVA with Dunnett’s post test. *P < 0.05. (G) Representative electrophysiological trace and (H) representative histological images of cross-sectioned sciatic nerves of a WT treated with PBS, a C22 treated with PBS, or a C22 treated with 100 mg/kg of ASO1 for 9 weeks. Scale bar: 5 μm. (I) Quantification of percentage of myelinated, percentage of unmyelinated, and percentage of onion bulb axons. One-way ANOVA with Dunnett’s post test was used to compare between C22 treated with PBS or ASO1 and WT treated with PBS. ***P < 0.001