Ionis Pharmaceuticals Inc., Carlsbad, California, USA.
Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
J Clin Invest. 2018 Jan 2;128(1):359-368. doi: 10.1172/JCI96499. Epub 2017 Dec 4.
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.
腓骨肌萎缩症 1A 型（CMT1A）是由外周髓鞘蛋白 22（PMP22）重复引起的，是最常见的遗传性周围神经病。CMT1A 的特征是脱髓鞘和轴突丢失，这导致患者运动神经传导速度（MNCV）减慢和复合肌肉动作电位（CMAP）降低。目前尚无针对这种疾病的已知治疗方法。在这里，我们在 2 种 CMT1A 小鼠模型中显示，反义寡核苷酸（ASO）可有效抑制受累神经中的 PMP22 mRNA。值得注意的是，在疾病发作后开始 ASO 治疗可恢复髓鞘、MNCV 和 CMAP，使其接近 WT 动物的水平。除了与疾病相关的基因表达网络在 ASO 治疗后得到恢复外，我们还通过转录组分析鉴定了潜在的疾病生物标志物。此外，我们证明了 ASO 治疗大鼠皮肤活检中 PMP22 mRNA 的减少是评估 ASO 治疗反应中靶标结合的合适生物标志物。这些结果支持 ASO 作为 CMT1A 潜在治疗方法的使用，并阐明了未来临床试验中可能用于疾病和靶标结合的生物标志物。
