What do we know about CT38/Urocortin II?

[nandixon]

To update this thread, Cortene’s patent application for the use of the corticotropin-releasing factor receptor subtype 2 (CRFR2) agonist CT38 in ME/CFS was published 26 April 2018 here.

Under the Description tab it can be seen that CT38 had the original designation of Procter & Gamble PG-873638 (the closely related PG-873637 became Cortene’s CT37).

The peptide CT38 contains 40 amino acids and its sequence is given in Figure 11 under the Drawings tab as:

ZGPPISIDLP FQLLRKVIEI EKQEKEKQQA ANNARLLDTI

Urocortin 2 has 38 amino acids and is:

IVLSLDVPIG LLQILLEQAR ARAAREQATT NARILARV

From this study, Modifications of the human urocortin 2 peptide that improve pharmacological properties, it seems apparent that CT38 was the result of a research effort that successfully combined the selectivity of urocortin 2 for CRFR2 with the in vivo potency of a 39-amino acid frog peptide known as sauvagine, which has the sequence:

ZGPPISIDLS LELLRKMIEI EKQEKEKQQA ANNRLLLDT

(Sauvagine itself does not have good selectivity.)

 

[HTester]

Several patients have said to me that they see the Cortene hypothesis and the metabolic trap hypothesis as closely related. The two hypotheses both refer to Raphe nuclei and serotonergic neurons, but that seems to me to be the end of the similarity. So I'm trying to get up to speed on CT38.

I'm hoping some of you who have followed Cortene from the beginning can help me understand the proposed mechanism of action of CT38.

@nandixon cites the Cortene patent application describing CT38 as a CRFR2 agonist. Other sources, such as the Cortene website, describe the mechanism of action of CT38 as "downregulation of the CRFR2 receptor."

Should we infer that CT38 is aimed at overstimulation of CRFR2 so that transcriptional feedback control systems will downregulate CRFR2 transcription and thus reduce the CRFR2-G-protein-signaling in the CRFR2-expressing cells?

This kind of agonist-induced down-regulation is a well known physiological phenomenon so it's not an unreasonable proposal, but I'm wondering if there has been a discussion of what will happen during the initial 3-hour infusions of the receptor agonist, especially since the Cortene website says, "Overstimulating this receptor induces many of the symptoms of ME/CFS in healthy animals, and we have developed a therapeutic candidate (CT38) that downregulates the receptor."

In other words, I'm just trying to get clear on the proposed chain of mechanistic molecular events that, if all goes according to plan, will take place in the patient's body in response to an infusion of a CRFR2 receptor agonist (CT38).

What do you think?

 

[nandixon]

@HTester, The CT38, at a certain minimum threshold dose, simply causes the CRFR2 receptors to internalize into the cell from the cell membrane, in a process called endocytosis. (Cortene believes the CRFR2 receptors are essentially “stuck” in the membrane position in ME/CFS and thus subject to continual undesirable activation, I think.)

Under the Description tab of Cortene’s patent application, they go into detail about the use of the drug. Basically the idea is to infuse the drug at a high enough concentration to effect the internalization of the CRFR2 receptors but at a slow enough rate to minimize side effects to the patient. They begin with an overview of the process starting at clause 77:

77. The controlled release dose to achieve sustained CRFR2 stimulation, thereby causing receptor endocytosis, is determined by 4 main factors: (i) CRFR2 agonist potency; (ii) the dose must achieve and maintain a plasma concentration at or above the minimum endocytotic concentration (-1.1-1.9 ng/ml of CT38 in healthy humans, see Example 7); (iii) the minimum endocytotic concentration must be maintained over a period of -2-3 hours (based on at least 15 minutes in vitro); and (iv) the rate of dosing must not be so high as to induce plasma concentrations associated with side effects by bolus dosing (i.e., not greater than -0.2 ng/ml of CT38 in any 15-minute period in healthy humans, see Figure 9C). However, as noted above, both the side effect-inducing dose and the ultimate level of endocytosis required for therapeutic effect will depend upon the extent to which CRFR2 is up-regulated in a given patient at the onset of treatment. These constraints define a dosing paradigm whereby the greater the symptom severity, the lower will be the initial controlled release dose level to be administered, but the longer the controlled release dose will have to be maintained to achieve therapeutic effect.

 

[nandixon]

Here is more on Cortene's theory from the Summary section of the patent (under the Description tab):

SUMMARY

The present disclosure considers that SEID [ME/CFS] arises from a sufficiently intense or prolonged stress that brings about a maladaptation of the stress response, in which the corticotropin-releasing factor receptor subtype 2 (CRFR2) is up-regulated and relocated to the membranes of serotonin (5-hydroxytryptamine or 5HT) neurons in the brain. In such a configuration, a subsequent minor stress induces the response of a major stress, stimulating, rather than inhibiting, the release of 5HT in the brain. The resulting excess of 5HT plausibly explains the symptoms of SEID patients. The present disclosure proposes a treatment paradigm involving the use of a CRFR2 agonist as a therapeutic to reverse CRFR2 maladaptations, which may be curative. The present disclosure provides guidance on the form and extent of the proposed treatment.

In certain subregions of the brain, including the raphe nuclei (in the brain stem and source of 5HT in the brain) and the limbic system (i.e., hippocampus, amygdala, bed nucleus of stria terminalis or BNST, fornix, parahippocampal gyrus, thalamus, hypothalamus, cingulate gyrus, ventral tegmental area, septum, periaqueductal gray, nucleus accumbens, etc.), stress can cause the up-regulation and relocation of CRFR2 to the plasma membranes of the 5HT neurons, with concomitant internalization of CRFR1 to the cytosol (see, e.g. Waselus et al. Biol Psychiatry. 66(2009):76-83 and Wood et al. Biol Psychiatry. 73(2013): 1087-94). This is a normal adaptive process, but if the stress is intense or prolonged enough it can desensitize the mechanisms that would ordinarily restore homeostasis, thereby preventing the changes in CRFR2 (and CRFR1) from being restored to their basal configurations. Under subsequent stress, such maladaptations change the release of 5HT and other neurotransmitters, effectively causing the system to react to minor stress as though it were a major stress. Based upon animal models in which stress in young mice induces a persistent up-regulation of CRFR2 in the BNST of the adult mice, the present disclosure postulates that SEID is the result of such stress-induced up-regulation/relocation of CRFR2 in the previously mentioned subregions of the brain, and that these changes persist long after the triggering stress has abated (see, e.g. Victoria et al. Psychoneuroendocrinology. 38(2013):3015-28). This leads to a maladapted stress response and an inability to restore CRFR2 to the pre-disease configuration. The present disclosure describes methods of utilizing CRFR2 agonists to reverse the maladaptation and restore the pre-disease configuration.

 

[Hip]

I'm hoping some of you who have followed Cortene from the beginning can help me understand the proposed mechanism of action of CT38.

There is a post here which compares the mechanism of Cortene to the similar mifepristone protocol used by Dr Nancy Klimas (which I hope is correct).

 

[wigglethemouse]

@HTester Cort wrote a series of articles as well
Part 1 : https://www.healthrising.org/blog/2...ialed-chronic-fatigue-syndrome-mecfs-soon-pt/
Part 2 : https://www.healthrising.org/blog/2018/02/17/cortene-chronic-fatigue-syndrome-hypothesis/
Part 3 : https://www.healthrising.org/blog/2...ue-syndrome-me-cfs-pt-iii-the-clinical-trial/
Clinical Trial : https://www.healthrising.org/blog/2018/07/14/cortene-chronic-fatigue-syndrome-me-cfs-drug-trial-begins/
Gov trial listing : https://clinicaltrials.gov/ct2/show/NCT03613129

Reading a post on here (link to patient blog who is participating) I believe the trial started, and then stopped to change the protocol, and restarted towards the end of the year.

 

[perrier]

@HTester Cort wrote a series of articles as well
Part 1 : https://www.healthrising.org/blog/2...ialed-chronic-fatigue-syndrome-mecfs-soon-pt/
Part 2 : https://www.healthrising.org/blog/2018/02/17/cortene-chronic-fatigue-syndrome-hypothesis/
Part 3 : https://www.healthrising.org/blog/2...ue-syndrome-me-cfs-pt-iii-the-clinical-trial/
Clinical Trial : https://www.healthrising.org/blog/2018/07/14/cortene-chronic-fatigue-syndrome-me-cfs-drug-trial-begins/
Gov trial listing : https://clinicaltrials.gov/ct2/show/NCT03613129

Reading a post on here (link to patient blog who is participating) I believe the trial started, and then stopped to change the protocol, and restarted towards the end of the year.

Sorry dear wigglemouse, but I’m having trouble understanding your last paragraph.
Are you referring to something someone on PR posted? I’m trying to follow this thread closely. Thanks.

 

[wigglethemouse]

Sorry dear wigglemouse, but I’m having trouble understanding your last paragraph.
Are you referring to something someone on PR posted? I’m trying to follow this thread closely. Thanks.

@perrier
This is the blog by one of the participants from 11 Nov 2018 stating trial had restarted. I understand that they will not be posting progress due to clinical trial confidentiality.
http://birdbeeme.com/its-here-cortene-trial-infusions/

 

[Critterina]

Frontiers | Acute Corticotropin-Releasing Factor Receptor Type 2 Agonism Results in Sustained Symptom Improvement in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | Frontiers in Systems Neuroscience

What I understand is that they started at too high a dosage. When they tried different dosages, they found one that worked, but in the end, only 10 patients/subjects had been put on that protocol.