Targeting the colony stimulating factor 1 receptor alleviates two forms of Charcot-Marie-Tooth disease in mice
Targeting the colony stimulating factor 1 receptor alleviates two forms of Charcot-Marie-Tooth disease in mice
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DOI：
10.1093/brain/awv240
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发表时间：
2015-11-01
期刊：
影响因子：
14.5
通讯作者：
Martini, Rudolf
中科院分区：
文献类型：
--
作者：
Klein, Dennis;Patzko, Agnes;Martini, Rudolf
Charcot-Marie-Tooth 1型神经病是由雪旺细胞相关基因突变引起的周围神经系统遗传性疾病。通常情况下，目前尚无病因治疗方法。本小组先前的临床前数据强调了不同的Charcot-Marie-Tooth 1型神经病常见的低级别继发性炎症作为疾病放大器。在目前的研究中，我们测试了几种可用的临床药物中的一种，通过抑制集落刺激因子1受体（CSF1R）来靶向巨噬细胞。我们在这里表明，在两种不同的charco - marie - tooth型神经病小鼠模型中，口服CSF1R的系统性短期和长期抑制导致神经巨噬细胞数量大幅下降约70%，并显著减少典型的组织病理学和功能改变。有趣的是，在主要的x连锁型1型charcot - mari - tooth神经病（遗传性神经病的第二常见形式）模型中，巨噬细胞消融有利于维持轴突完整性和轴突再生，从而在野生型小鼠范围内保留肌肉神经支配，增加肌肉动作电位振幅和肌肉力量。在另一个模拟由P0 （MPZ）基因剂量降低引起的轻度脱髓鞘相关的charcot - mar- tooth 1型神经病变的模型中，巨噬细胞阻断可改善髓磷脂的保存，增加肌肉动作电位振幅，改善神经传导速度和改善肌肉力量。这些观察结果表明，放大疾病的巨噬细胞可以在受影响的神经中产生多种不良反应，这些不良反应可能归结为共同的临床特征。令人惊讶的是，对模拟Charcot-Marie-Tooth型1A神经病变的小鼠模型的治疗也引起巨噬细胞阻断，但没有导致神经性或临床改善，很可能是由于这种早发性疾病模型的治疗开始较晚。总之，我们的研究表明，通过口服CSF1R抑制剂靶向周围神经巨噬细胞可能为至少两种不同形式的目前无法治疗的Charcot-Marie-Tooth 1型神经病提供一种高效安全的治疗选择。
Charcot-Marie-Tooth type 1 neuropathies are inherited disorders of the peripheral nervous system caused by mutations in Schwann cell-related genes. Typically, no causative cure is presently available. Previous preclinical data of our group highlight the low grade, secondary inflammation common to distinct Charcot-Marie-Tooth type 1 neuropathies as a disease amplifier. In the current study, we have tested one of several available clinical agents targeting macrophages through its inhibition of the colony stimulating factor 1 receptor (CSF1R). We here show that in two distinct mouse models of Charcot-Marie-Tooth type 1 neuropathies, the systemic short-and long-term inhibition of CSF1R by oral administration leads to a robust decline in nerve macrophage numbers by similar to 70% and substantial reduction of the typical histopathological and functional alterations. Interestingly, in a model for the dominant X-linked form of Charcot-Marie-Tooth type 1 neuropathy, the second most common form of the inherited neuropathies, macrophage ablation favours maintenance of axonal integrity and axonal resprouting, leading to preserved muscle innervation, increased muscle action potential amplitudes and muscle strengths in the range of wild-type mice. In another model mimicking a mild, demyelination-related Charcot-Marie-Tooth type 1 neuropathy caused by reduced P0 (MPZ) gene dosage, macrophage blockade causes an improved preservation of myelin, increased muscle action potential amplitudes, improved nerve conduction velocities and ameliorated muscle strength. These observations suggest that disease-amplifying macrophages can produce multiple adverse effects in the affected nerves which likely funnel down to common clinical features. Surprisingly, treatment of mouse models mimicking Charcot-Marie-Tooth type 1A neuropathy also caused macrophage blockade, but did not result in neuropathic or clinical improvements, most likely due to the late start of treatment of this early onset disease model. In summary, our study shows that targeting peripheral nerve macrophages by an orally administered inhibitor of CSF1R may offer a highly efficacious and safe treatment option for at least two distinct forms of the presently non-treatable Charcot-Marie-Tooth type 1 neuropathies.