VCP/p97 inhibitor CB-5083 modulates muscle pathology in a mouse model of VCP inclusion body myopathy.
VCP/p97 inhibitor CB-5083 modulates muscle pathology in a mouse model of VCP inclusion body myopathy.
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DOI：
10.1186/s12967-021-03186-6
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发表时间：
2022-01-08
影响因子：
7.4
通讯作者：
Kimonis V
中科院分区：
文献类型：
--
作者：
Cheng C;Weiss L;Leinonen H;Shmara A;Yin HZ;Ton T;Do A;Lee J;Ta L;Mohanty E;Vargas J;Weiss J;Palczewski K;Kimonis V
含缬酪肽蛋白（VCP）的致病性功能获得性变异会导致一种独特的疾病，其特征为包涵体肌病伴早发性佩吉特骨病和额颞叶痴呆（也称为多系统蛋白病（MSP））。先前在VCP疾病的果蝇模型中的研究表明，使用VCP抑制剂治疗可减轻疾病病理。早期的VCP抑制剂存在脱靶效应且治疗效力相对较低。新一代的VCP抑制剂需要在VCP疾病的小鼠模型中进行评估。在本研究中，我们使用源自VCP患者的成肌细胞和VCP疾病的动物模型测试了一种新型高效的VCP抑制剂CB - 5083的安全性和有效性。
首先，我们通过蛋白质印迹法分析了CB - 5083对源自患者的成肌细胞中典型疾病自噬和TDP - 43情况的影响。接下来，我们确定了CB - 5083在小鼠中的最大耐受剂量，并使用15mg/kg的CB - 5083对2月龄的VCPR155H/R155H小鼠治疗5个月。我们每月通过转棒实验分析运动功能；并使用蛋白质印迹法和免疫组织化学评估终点血液毒理学以及肌肉和大脑的病理情况，包括自噬和TDP - 43情况。我们还对12月龄的VCPR155H/+小鼠治疗6个月并进行了类似的分析。最后，我们使用视网膜电图评估了CB - 5083对慢性治疗的VCPR155H/155H小鼠视网膜功能的潜在副作用。
使用源自患者的成肌细胞进行的体外分析证实，CB - 5083能够调节自噬途径中蛋白质的表达。我们发现，慢性CB - 5083治疗在携带患者特异性VCP变异体R155H的纯合子小鼠中具有良好的耐受性，并且能够改善该疾病的肌肉病理特征。与VCP相关的病理生物标志物，如升高的TDP - 43和p62水平，显著降低。最后，为了解决先前在一项肿瘤临床试验中观察到的CB - 5083对视觉功能的潜在不良影响，我们分析了使用中等剂量的CB - 5083治疗5个月的小鼠的视网膜功能，并记录到没有永久性眼毒性。
总之，这些发现表明，中等剂量长期使用CB - 5083是安全的，并且能够改善与VCP疾病相关的肌肉病理。我们的结果提供了具有转化相关性的证据，即VCP抑制剂可能对VCP疾病的治疗有益。
网络版包含补充材料，可在10.1186/s12967 - 021 - 03186 - 6获取。
Pathogenic gain of function variants in Valosin-containing protein (VCP) cause a unique disease characterized by inclusion body myopathy with early-onset Paget disease of bone and frontotemporal dementia (also known as Multisystem proteinopathy (MSP)). Previous studies in drosophila models of VCP disease indicate treatment with VCP inhibitors mitigates disease pathology. Earlier-generation VCP inhibitors display off-target effects and relatively low therapeutic potency. New generation of VCP inhibitors needs to be evaluated in a mouse model of VCP disease. In this study, we tested the safety and efficacy of a novel and potent VCP inhibitor, CB-5083 using VCP patient-derived myoblast cells and an animal model of VCP disease. First, we analyzed the effect of CB-5083 in patient-derived myoblasts on the typical disease autophagy and TDP-43 profile by Western blot. Next, we determined the maximum tolerated dosage of CB-5083 in mice and treated the 2-month-old VCPR155H/R155H mice for 5 months with 15 mg/kg CB-5083. We analyzed motor function monthly by Rotarod; and we assessed the end-point blood toxicology, and the muscle and brain pathology, including autophagy and TDP-43 profile, using Western blot and immunohistochemistry. We also treated 12-month-old VCPR155H/+ mice for 6 months and performed similar analysis. Finally, we assessed the potential side effects of CB-5083 on retinal function, using electroretinography in chronically treated VCPR155H/155H mice. In vitro analyses using patient-derived myoblasts confirmed that CB-5083 can modulate expression of the proteins in the autophagy pathways. We found that chronic CB-5083 treatment is well tolerated in the homozygous mice harboring patient-specific VCP variant, R155H, and can ameliorate the muscle pathology characteristic of the disease. VCP-associated pathology biomarkers, such as elevated TDP-43 and p62 levels, were significantly reduced. Finally, to address the potential adverse effect of CB-5083 on visual function observed in a previous oncology clinical trial, we analyzed retinal function in mice treated with moderate doses of CB-5083 for 5 months and documented the absence of permanent ocular toxicity. Altogether, these findings suggest that long-term use of CB-5083 by moderate doses is safe and can improve VCP disease-associated muscle pathology. Our results provide translationally relevant evidence that VCP inhibitors could be beneficial in the treatment of VCP disease. The online version contains supplementary material available at 10.1186/s12967-021-03186-6.
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影响因子：
3.5
作者：
Hatzimouratidis, Konstantinos;Salonia, Andrea;Khera, Mohit
通讯作者：
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DOI：
10.1124/jpet.120.000486
发表时间：
2021-07-01
影响因子：
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作者：
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通讯作者：
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作者：
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影响因子：
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