Developed countries, including Japan, are facing an issue on aging population. Finding solutions to “aging” in healthcare is an urgent issue not only medically but also socially.
Our company wants to clarify the senescence of cells at the molecular level, develops new drugs to treat diseases associated with the aging of tissues and individuals, and will develop medical treatments to improve human aging in the future.
Except for tumor cells, living cells cannot grow indefinitely due to a phenomenon called cell senescence (Replicative senescence). This phenomenon involves shortening the telomere length of the chromosome, as well as cellular aging factors such as p53. Interestingly, senescent cells have been shown to express extremely high levels of the plasminogen activator inhibitor (PAI) -1 molecule in addition to p53.
High expression of PAI-1 was reported not only in cells but also in aged tissues and individuals (klotho mice and humans with Werner's syndrome; a famous progeria disease). In a collaborative study between our company and the Northwestern University School of Medicine, an inhibition of the expression and activity of PAI-1 at the gene or protein level in the klotho mouse, a famous aging model, resulted in an improvement of aging in cells, tissues and individuals.
With age, cancer and diseases in blood vessels (arteriosclerosis), lungs (emphysema, chronic obstructive pulmonary disease), metabolism (diabetes, obesity), kidneys (chronic kidney disease), bones and joints (osteoporosis, osteoarthritis), and the brain (cerebrovascular disorder, Alzheimer's disease / dementia) develop.
For more than a decade, research has been conducted on the health of older Christian Amish people living in the Midwest of the United States. In a joint research with Northwestern University School of Medicine and Tohoku University, we surveyed 177 people in the Amish community, and 43 people who did not have the PAI-1 gene live 10 years longer and are less susceptible to diseases such as diabetes compared to 134 people who did have the PAI-1 gene.
This fact was reported in many newspapers, including the New York Times in November 2017. "They don't just live longer. They live healthier. Ideal for longevity." said the principal investigator, Douglas Vaughan, Professor and Chairman, Department of Medicine, Northwestern University Feinberg School of Medicine. This epidemiological finding in humans was consistent with experimental results in cells and mice.
PAI-1 is a molecule required for thrombus formation and has been studied as a target for the treatment of thrombosis. However, in recent years, its involvement in “aging” or various diseases associated with aging has been strongly suggested as a causative molecule.
Unfortunately, drugs that can inhibit the activity of the human PAI-1 molecule have not been clinically utilized. We wondered if we could manage to develop a PAI-1 inhibitor as an approved drug, which has the potential to treat a series of diseases associated with aging.
Based on the crystal structure of the human PAI-1 molecule, we speculated drugs (small molecules) that could inhibit the activity using the computerized engineering. And in the next decade or more, we have synthesized more than 1,300 new compounds that can inhibit the PAI-1 activity. From detailed evaluations of the inhibitory activities, the safety, and the pharmacokinetics of these compounds, we finally obtained a candidate for clinical development called RS5614.
We completed the animal safety studies and subsequently a human safety study (Phase 1 study) on RS5614. Currently, we are conducting clinical trials for the treatment of cancer (chronic myelogenous leukemia, malignant melanoma and COVID-19 infections(ARDS)).
In the future, we plan to gradually conduct research and development into age-related diseases such as metabolic diseases.