Abstract
BackgroundMyalgic 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.Materials and MethodsThis open-label trial tested the safety, tolerability and efficacy of an acute 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.ResultsME/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%, p = 0.009), with all monitored symptoms improving.ConclusionThe 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.Clinical Trial RegistrationClinicalTrials.gov, identifier NCT03613129.
Highlights
Myalgic Encephalomyelitis/Chronic Fatigue SyndromeMyalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease affecting ∼20 million worldwide
Adverse events were generally mild, resolved without intervention, and difficult to distinguish from ME/CFS symptoms, supporting a corticotropin-releasing factor receptor type 2 (CRFR2) role in the disease
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
Summary
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease affecting ∼20 million worldwide It can be triggered by infection, traumatic life events, chemicals, toxins, immunizations, anesthetics, physical trauma, among others (Chu et al, 2019). Its major symptoms include profound fatigue (described as “concrete limbs,” “crushing gravity,” “not tired”), musculoskeletal pain, cognitive impairment (“brain fog”), orthostatic intolerance (OI), flu-like symptoms and un-refreshing sleep (Chu et al, 2018, 2019). These are exacerbated by any kind of stimulation, including physical, cognitive, emotional (Chu et al, 2018) and even postural change (van Campen et al, 2021), referred to as post-exertional malaise (PEM). The authors propose utilizing agonist-mediated receptor endocytosis to downregulate CRFR2
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