Methods of treating diseases resulting from a maladapted stress response (Cortene's patent application)

I know this has been discussed before, but Cortene updated the patent application pertaining to their neuropeptide on Oct 10.

Disconcerting that Cortene's model of ME is virtually identical to Wessely's (that of a single/unitary functional somatic syndrome manifesting variously as ME, FM, IBS, etc.)

 

The model of ME described is a serious neuro-biological maladaptation, not the “old wine in new bottles”, not-a-real-disease Wessely model. In accepting that ME is a neuro-immune or neurological illness, I accept it involves the brain.

 

It might appear that way, but this is very much a psychiatric model of ME.

I did intend to write something in-depth dissecting this patent and dig deeply into the literature around CRF, but it seems highly unlikely that their work will progress beyond a Phase II trial, and, in any event, I'm really not sure this forum is the right place for it.

A few quick, brief observations. From the patent:

"this receptor is up-regulated and relocated to the neuronal membranes of key regions of the brain including the raphe nuclei. . ."

Although CRFergic dysregulation has been posited to be a component of certain psychiatric disorders (including depression and PTSD), and more specifically that upregulation of the CRF receptor 2 in the raphe nuclei is known to be implicated in PTSD, there is no evidence that I can find implicating such dysregulation in the generation of fatigue states.

"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"

There are obviously no animal models of ME (short of infecting a million mice with EBV, finding the few that exhibit severely disproportionate post-exertional malaise after 6 months, and excluding all other murine diseases!). Upregulation of CRFR2 in the BNST is implicated in the threat response and appears to correlate with expressions of anxiety and fear-related behaviours. The animal model to which they refer is a straightforward and well-studied chronic-stress model that in no way parallels the typical course of ME. (Perhaps some other criticisms to be made: has Cortene performed ME/control between-group comparisons of CRF2 in peripheral mononuclear cells, or even measured endogenous CRF levels in ME patients' CSF? There seems to be no mention of anything along these lines, and I'm confused as to why they would licence a peptide from Proctor and Gamble before performing more exploratory work with ME patients.)

If Cortene's model were plausible, wouldn't we expect to see not only highly elevated situational fear & anxiety in ME patients, but specific PTSD-esque behaviours, such as hyperarousal or exaggerated startle responses?

In any event, the model described is clearly congruent with the fear-conditioning model of PTSD. There is no substantive immunological component proposed; it is a model for a postulated psychiatric disorder.

Well, symptoms such as `brain fog' cannot be other than neurological by definition, but there is surprisingly little evidence of ME being neuroimmune in the strict sense of that term; I agree that it would appear likely, given the sheer number of post-infectious cases, but who knows? Nature seems to so often fly in the face of all conventional assumptions.

Lastly, I wonder if Lucinda Bateman, the PI, accepts their framing of ME as a manifestation of a `functional somatic syndrome'?

 

Thanks @glimpsesofme, I really enjoyed reading your response. My thinking on ME as a neuro-immune illness is of a receptor immune response which results in a messaging defect, while non-immune ME (or CFS) is of the neuro-biological maladaptation described above. I think it is possible to recover from ME without a persistent neuro-biological maladaptation, but I know it's also possible to not recover from the immune response, which is why I think it's so important to sub-group and test patients.

 

Looking at the graphs showing how different doses affect various aspects of rat physiology and behaviour, this does not look promising.

The greater water retention (delayed urination) could be generally desirable in ME/CFS.

An increase in maximum heart rate also, but only if the resting average heart rate doesn't go up. The graph only shows max heart rate.

Blood pressure going down seems bad. Patients tend to be on the lower end of normal already.

What does it mean that respiratory rate and minimum temperature go down?

There is a big reduction in activity levels of the rats. That seems bad.