Cutamesine is a highly selective sigma-1 receptor agonist. We have developed this compound for the treatment of CNS diseases. We have performed clinical studies of cutamesine for the treatment of stroke and depression. However, due to recent academic research findings, we have reselected ALS as the most appropriate target disease for cutamesine. We have also discovered cutamesine has therapeutic effects on some ocular diseases.
ALS is a neurodegenerative disorder in which motor neurons are specifically damaged and muscles become weakened. Disease progression is rapid and patients die within an average of 3–5 years after diagnosis. Currently, there is no drug available to cure ALS, although a compound named riluzole is approved for its treatment. Therefore, a new effective therapeutic drug for the treatment of ALS is urgently needed.
In the last several years, more than 10 papers have appeared describing a relationship between ALS and sigma-1 receptor dysfunction. While the sigma-1 receptor functions in various cell types, this protein seems particularly important for motor neurons. We have already confirmed the protective effects of cutamesine on motor neurons and observed beneficial effects in ALS model mice.
Although we have not performed a clinical trial with ALS patients, we observed some stimulatory effects of cutamesine on motor function recovery in stroke patients. While the etiology of stroke is different from ALS, the difficulties of movement of limbs in stroke patients are caused by damage to motor neurons. Therefore, it is likely our observations in stroke patients are due to the effects of cutamesine on motor neuron cells. Therefore, cutamesine is highly expected to show beneficial effects in ALS patients.
To date, our sigma-1 receptor research has focused on the nervous system. However, this protein is found ubiquitously in the body. In ocular tissues, the sigma-1 receptor exists not only in the optic nerve but also in non-neuronal cells. Since we have tremendous experience and knowledge in the ophthalmic field, we are also investigating the sigma-1 receptor function in ocular tissues. At present, we are investigating retinitis pigmentosa (RP) and age-related macular degeneration (AMD) as target diseases. RP is caused by gradual degradation of photoreceptor cells, while AMD is caused by dysfunction and apoptosis of retinal pigment epithelial cells. Therefore, as the sigma-1 receptor may protect these cell types from stress and prolong their survival, sigma-1 receptor agonists may be beneficial for treating RP and AMD. We will continue non-clinical research into the effects of cutamesine on these ocular disorders.
It is not easy to determine the clinical doses of CNS drugs. Dosages are usually determined by patient responses during dose-finding clinical studies. However, in the case of cutamesine, we were able to determine the optimal dose for humans theoretically.
One of the important features of receptor proteins is their “saturability.” At high ligand concentration, almost all receptor protein molecules are bound, and therefore, saturated by the ligand. When a very small quantity of 11C-labeled cutamesine is administered to human or animals, the labeled compound can bind to sigma-1 receptor in the brain. However, if excessive unlabeled cold cutamesine is administered in advance, the labeled molecule cannot bind to the receptor sufficiently because the receptors are already occupied with cold cutamesine. The image below shows the positron emission tomography (PET) scan of 11C-labeled cutamesine in a human brain. The red and yellow colored regions indicate the binding of 11C-labeled cutamesine (left image). When a volunteer takes cold cutamesine orally in advance, the compound reaches the brain and binds to the sigma-1 receptor. When 11C-labeled cutamesine is administered 2 h later, the labeled molecule cannot bind to the receptor because cold molecules are already occupying the ligand-binding sites. From this clinical study, we found that even 20 h after oral administration, cutamesine remains at the receptor site. Therefore, from these studies, we were able to conclude that a 3 mg once-daily dosing of cutamesine was optimal for CNS disorders.
- 2 hours after
- 20 hours after
This PET study also showed that cutamesine remains bound to the sigma-1 receptor for a long period of time. In other words, non-specific binding of cutamesine to other proteins in the brain is very low. Compounds with high non-specific binding can sometimes cause adverse events in brain tissues. Therefore, our initial studies show that cutamesine does not accumulate in brain tissues and shows low toxicity.