Unraveling diseases of dysregulation

Cortene is a clinical stage biopharmaceutical company, targeting homeostasis and the limbic system to develop therapies for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID.


  1. Under homeostatic threat, CRFR2 upregulates to increase serotonin (5HT) in the limbic system
  2. CRFR2 can fail to downregulate, if 5HT becomes excessive
  3. CRFR2 agonism can downregulate the receptor

CRFR2=corticotropin-releasing factor receptor type 2

The Limbic System

Long relegated to an emotional role, it has become increasingly evident that the limbic system is at the core of maintaining homeostasis (steady state). It receives input from, and outputs to, the sensory, autonomic, endocrine, metabolic and immune systems (among others). It relies upon generating a specific serotonin signal (modulating other neurotransmitters as necessary) to control homeostasis.


In response to any threat to homeostasis, corticotropin-releasing factor (CRF) acts via 2 receptors (CRFR1 and CRFR2) to control serotonin in the limbic system and cord. When the threat subsides these receptors return to their basal configuration.

Intense or prolonged threats to homeostasis can permanently upregulate CRFR2. This disrupts serotonin, leading to a deregulation of body systems and processes, characteristic of many acquired chronic diseases.


Cortene’s treatment approach mimics a natural process that prevents neurons (or cells) from becoming over-excited. This process, called endocytosis or downregulation, overstimulates the receptors, causing them to leave the membrane and internalize in the neuron. Cortene’s proprietary CRFR2 agonist, CT38, has been shown to achieve downregulation

Cortene’s hypothesis, treatment approach and clinical trial are described more thoroughly in our recent publication.


CT38 is a potent, short-lived, peptide agonist selective for CRFR2. It is comprised entirely of naturally-occurring amino acids.

It was tested in animals and in healthy humans in a Phase 1 clinical trial. These studies have defined the safety profile of CT38 in humans and show that CT38 only lasts a few hours in the body.


A recent Phase 1/2 clinical trial to Investigate CT38 in ME/CFS patients (InTiME) tested various doses to understand how Cortene’s novel treatment approach might work (registered on ClinicalTrials.gov). Preliminary data support the following statements:

  1. As predicted, CRFR2 appears to be upregulated in ME/CFS patients (relative to healthy human subjects).
  2. Side-effects were mostly minor and resolved without intervention.
  3. A short treatment (~10 hours) with CT38 resulted in symptom improvements that lasted at least 28 days (the monitoring period of the trial).
  4. In the most effective dosing group, symptom improvement was:
    • substantial (average 26%);
    • effective on all monitored symptoms;
    • immediate (within 1-2 days of treatment);
    • persistent (at least 28 days); and
    • statistically significant (p=0.009).
  5. Symptom improvement was related to total dose, suggesting that increasing the total dose could reduce symptoms further.

Cortene’s hypothesis, treatment approach and clinical trial are described more thoroughly in our recent publication.