Pereira Gerard, Gillies Hunter, Chanda Sanjay, Corbett Michael, Vernon Suzanne D, Milani Tina, Bateman Lucinda
Cortene Inc., Burlingame, CA, United States.
Bateman Horne Center, Salt Lake City, UT, United States.
Front Syst Neurosci. 2021 Sep 1;15:698240. doi: 10.3389/fnsys.2021.698240. eCollection 2021.
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex multi-symptom disease with widespread evidence of disrupted systems. The authors hypothesize that it is caused by the upregulation of the corticotropin-releasing factor receptor type 2 (CRFR2) in the raphé nuclei and limbic system, which impairs the ability to maintain homeostasis. The authors propose utilizing agonist-mediated receptor endocytosis to downregulate CRFR2.
This open-label trial tested the safety, tolerability and efficacy of an dose of CT38s (a short-lived, CRFR2-selective agonist, with no known off-target activity) in 14 ME/CFS patients. CT38s was subcutaneously-infused at one of four dose-levels (i.e., infusion rates of 0.01, 0.03, 0.06, and 0.20 μg/kg/h), for a maximum of 10.5 h. Effect was measured as the pre-/post-treatment change in the mean 28-day total daily symptom score (TDSS), which aggregated 13 individual patient-reported symptoms.
ME/CFS patients were significantly more sensitive to the transient hemodynamic effects of CRFR2 stimulation than healthy subjects in a prior trial, supporting the hypothesized CRFR2 upregulation. Adverse events were generally mild, resolved without intervention, and difficult to distinguish from ME/CFS symptoms, supporting a CRFR2 role in the disease. The acute dose of CT38s was associated with an improvement in mean TDSS that was sustained (over at least 28 days post-treatment) and correlated with both total exposure and pre-treatment symptom severity. At an infusion rate of 0.03 μg/kg/h, mean TDSS improved by -7.5 ± 1.9 (or -25.7%, = 0.009), with all monitored symptoms improving.
The trial supports the hypothesis that CRFR2 is upregulated in ME/CFS, and that acute CRFR2 agonism may be a viable treatment approach warranting further study.
ClinicalTrials.gov, identifier NCT03613129.
肌痛性脑脊髓炎/慢性疲劳综合征（ME/CFS）是一种复杂的多症状疾病，有广泛证据表明其系统功能紊乱。作者推测，它是由中缝核和边缘系统中促肾上腺皮质激素释放因子受体2（CRFR2）上调引起的，这损害了维持体内平衡的能力。作者提议利用激动剂介导的受体内吞作用来下调CRFR2。
这项开放标签试验在14例ME/CFS患者中测试了一剂CT38s（一种短效、CRFR2选择性激动剂，无已知脱靶活性）的安全性、耐受性和疗效。CT38s以四个剂量水平之一（即输注速率为0.01、0.03、0.06和0.20μg/kg/h）皮下输注，最长输注10.5小时。疗效以治疗前/后28天每日总症状评分（TDSS）的变化来衡量，该评分汇总了13项患者报告的个体症状。
在先前的一项试验中，ME/CFS患者对CRFR2刺激的短暂血流动力学效应比健康受试者更为敏感，支持了CRFR2上调的假设。不良事件一般较轻，无需干预即可缓解，且难以与ME/CFS症状区分开来，支持CRFR2在该疾病中的作用。CT38s的急性剂量与平均TDSS的改善相关，这种改善持续存在（至少在治疗后28天），并且与总暴露量和治疗前症状严重程度相关。在输注速率为0.03μg/kg/h时，平均TDSS改善了-7.5±1.9（或-25.7%，P = 0.009），所有监测症状均有改善。
该试验支持了CRFR在ME/CFS中上调的假设，并且急性CRFR2激动作用可能是一种值得进一步研究的可行治疗方法。
ClinicalTrials.gov，标识符NCT03613129。
