Chronicle of Regeneration-Inducing Medicine™
Prologue
The idea of Regeneration-Inducing Medicine™ was conceived when our founder, Katsuto Tamai (current Director and Chief Scientific Officer), was seeing the patients suffering from an intractable disease, dystrophic epidermolysis bullosa. In this disease, the patient’s epidermis is detached from the dermis even with a small force, resulting in the daily loss of vast amounts of epidermal cells including epidermal stem cells from birth.
Our skin is composed of an outer epidermis, inner dermis, and basement membrane that connects them. In normal people, when the skin is injured, it repairs by itself because epidermal cells are supplied by the epidermal stem cells residing in the basement membrane. On the other hand, patients with dystrophic epidermolysis bullosa have a genetic mutation and cannot produce functional collagen type VII, a protein that plays a crucial role in binding the dermis and basement membrane. As a result, even a small force causes the detachment of the entire epidermis along with the basement membrane, leading to the loss of the epidermal stem cells.
While seeing the patients with dystrophic epidermolysis bullosa, Dr. Tamai wondered why the patient’s skin could continue to regenerate. Because a significant number of epidermal stem cells were lost in the patient, in theory, regeneration of the epidermis should be impossible. However, the patient’s skin continued to regenerate.
Witnessing this phenomenon, Dr. Tamai hypothesized that “stem cells that could become the epidermal stem cells might be supplied to the damaged skin from other part of the body through the bloodstream.” He also contemplated that if he found the endogenous molecule that triggered the stem cells to enter the bloodstream, he would be able to create a medicine from this molecule that would increase the stem cells in the bloodstream. He further envisioned that this would lead to an increased supply of the stem cells to the damaged tissue and regeneration ability of our body would be boosted.
Based on these ideas, Dr. Tamai started his research to realize Regeneration-Inducing Medicine™ with the goals of elucidating the mechanism of stem cell replenishment and creating a new drug for epidermolysis bullosa.
Elucidation of the Mechanism
Dr. Tamai advanced his research based on his hypothesis and found that a protein called HMGB1 plays a key role for the skin regeneration.
- The HMGB1 protein is usually localized in the nucleus of the cell. However, when epidermal cells die massively by necrosis, a large amount of HMGB1 protein is released from the nuclei and enters the bloodstream.
- The HMGB1 protein travels through the bloodstream and reaches the bone marrow. There, it activates ectodermal mesenchymal stem cells, which are unique population of mesenchymal stem cells and different from commonly known mesenchymal stem cells that are mesodermal.
- The activated ectodermal mesenchymal stem cells are mobilized and enter the bloodstream.
- The ectodermal mesenchymal stem cells circulate in the bloodstream and accumulate at the damaged tissue, guided by specific chemical signals (chemokines) released from the damaged tissue.
- With their inherent tissue repair ability, these ectodermal mesenchymal stem cells regenerate the damaged tissue such as skin.
The elucidation of this mechanism led to the concept of early-stage Regeneration-Inducing Medicine™: “if we administer the HMGB1 protein to a patient, we might be able to regenerate the damaged organ, harnessing the patient’s inner stem cells.”
Birth of First Regeneration-Inducing Medicine™
While there was hope that the administration of the HMGB1 protein could induce the regeneration of the damaged tissue through the recruitment of the stem cells, it was also revealed that the HMGB1 protein strongly activated natural immunity and triggered inflammation.
To resolve this problem, StemRIM analyzed which region of the HMGB1 protein mobilized the stem cells into the bloodstream. And we identified the domain in the HMGB1 protein that activated the stem cells and mobilized them into the bloodstream. This domain was located at a different place from the domain that induced inflammation.
Based on these findings, we chemically synthesized a peptide comprising only the domain of the HMGB1 protein that activated the stem cells and induced the regeneration, eliminating the domain that caused the inflammation. This peptide was named Redasemtide, the first “Regeneration-Inducing Medicine™”. We administered Redasemtide to epidermolysis bullosa model mice and witnessed that their skin regeneration was dramatically boosted. Moreover, while the epidermolysis bullosa mice usually died within three months without a treatment, the mice treated with Redasemtide survived for more than a year. Our multiple experiments also revealed that Redasemtide regenerated a large number of epidermal stem cells that had been lost by the disease.
We succeeded to demonstrate that the intravenous injection of Redasemtide induced the regeneration of the damaged tissue. This was a significant step towards the actualization of Regeneration-Inducing Medicine™.
From Lab to Clinic
Based on the results of the animal studies, we moved forward to prove the efficacy of the drug in humans. First, we conducted a clinical study with healthy adult males and confirmed that Redasemtide is safe for humans. Then, we conducted a next clinical study for dystrophic epidermolysis bullosa with 9 patients. Of the 9 patients, 7 patients showed an improvement in their symptoms, and 4 patients showed a significant improvement. Thereby, we confirmed that Redasemtide is effective for humans too. Furthermore, through the follow-up study to evaluate the duration of the effectiveness, we confirmed that the therapeutic effects of Redasemtide for dystrophic epidermolysis bullosa are not short-lived but long-lasting.
Other clinical trials have been conducted on Redasemtide for several other diseases, and we have further accumulated the results that Redasemtide is reliably safe and durably effective for humans. Accordingly, we have stepped forward to our vision in which Regeneration-Inducing Medicine™ provides a new treatment to the patients.
Future Outlook
Since its conception, we have believed that Regeneration-Inducing Medicine™ can be used not only for epidermolysis bullosa but also for a wide variety of diseases entailing tissue damage. In addition to epidermolysis bullosa, clinical trials are now ongoing for four other diseases: acute cerebral infarction, ischemic cardiomyopathy, knee osteoarthritis, and chronic liver disease. Moreover, we are earnestly conducting research on second-generation Regeneration-Inducing Medicine™ that follows Redasemtide.
Regeneration-Inducing Medicine™ has potential to be a game changer of regenerative medicine. We will keep pursuing our research and development with the vision of bringing smiles to the patients suffering from intractable diseases.
