July 10, 2014 12:00 am JST

Use of iPS cells raises hope for finding Alzheimer's cause

SHIGENORI ARAI, Nikkei staff writer

TOKYO -- Researchers at the Kyoto University Center for iPS Cell Research and Application are trying to find the mechanism of Alzheimer's disease by using induced pluripotent stem (iPS) cells created from patients' own bodies.

     They have discovered that pathologic features differ significantly among sufferers of the degenerative disease. The center's professor Haruhisa Inoue has launched a team with Fujifilm to develop medicine that will be effective to each of the features. The team is taking advantage of iPS cells' ability to grow into various kinds of body tissue.

     The team created iPS cells from the skin tissue of four Alzheimer's patients, who are in their 50s through 70s, and grew them into brain neurons. Team members were surprised to find that the neurons of each patient were different, although they were cultivated under the same conditions.

     Alzheimer's pathogenesis has three features: the accumulation of a protein called beta-amyloid inside or outside the brain cells; cells in a state that makes them die easily; and oxidative stress, a condition in which the concentration of cell-damaging active oxygen increases.

     Patients of familial Alzheimer's, who have genetic mutations that cause the disease, were found to have all three features. But some of the patients who have neither genetic mutations nor a family history of Alzheimer's were free of these features. The team also created neurons from three healthy people and found none of the features in them.

     The study showed that the pathogenesis greatly differs among Alzheimer's patients. It also indicated there can be no standard medicine. But the team sees a chance there.

     "We may be able to save many patients if we can develop medicine that works for each of them individually," professor Inoue said.

     This is no mere hunch -- Inoue has a strategy for future treatment. For patients with beta-amyloid plaques, drugs to curb the protein's concentration would be administered. Those with high levels of oxidative stress would get medicine that helps lower levels.

     This is where iPS cells come in again. It is practically impossible to extract live neurons from a brain. But the team believes that utilizing the iPS cell technique will enable them to see changes that must be happening inside a patient's body and develop medicine that suits each person's conditions.

Chance for new research

Drug studies using iPS cells are expected to get into full swing by 2020, and their results are likely to be applied to develop new medicine between 2020 and 2030.

     Inoue and Fujifilm launched a joint project this spring to study T-817MA, a medicine for dementia caused by Alzheimer's. The project aims to match the data of cultivated cells with the data to be obtained from clinical tests of candidate substances for new medicines.

     Kyoto University professor Shinya Yamanaka succeeded in creating the world's first iPS cells from mice in 2006. He proved in the following year that iPS cells can be created from human cells as well. The pioneering work earned him the Nobel Prize in physiology or medicine in 2012.

     In the initial years of research, the success rate of creating iPS cells was only 0.1%. The cells also carried a relatively high risk of becoming cancerous. The current success rate is over 20%. Yamanaka says the risk of cells turning cancerous is at negligible levels for clinical applications.

     The use of iPS cells is expected to be applied to regenerative medicine and contribute to drug development. As for regenerative medicine, the Japanese government-backed Riken institute plans to start a clinical study for age-related macular degeneration this summer. Similar studies on Parkinson's disease and severe blood disorders are likely to follow.

     One of iPS cells' prospective contributions to drug development is speeding up the selection of candidate substances for new medicine. Such cells made from skin or blood would be grown into matter that is linked to specific diseases, and candidate substances would be applied to it. Experiments are underway for developing medicine for amyotrophic lateral sclerosis and muscular dystrophy.

     Such cells are also likely to contribute to toxicity tests of prospective drugs. Even if a substance is effective, it cannot be used as a drug if it has strong side effects. Researchers hope that iPS-derived heart and liver cells will enable them to conduct toxicity tests under a condition close to that of a human body.

     Furthermore, iPS cells would be applied to clinical trials of candidate substances. Before starting trials, researchers can use iPS-derived cells to check if they react to a drug and find out differences among patients of the same illness. The aim is to develop medicines that target the particular symptoms of each patient.

     In conventional clinical trials, candidate substances that do not have a major effect on all patients have seldom been commercialized. But if such substances turn out to be effective to certain patients, they could be developed into new medicines. There are many chemical compounds that have failed to become drugs. Studies into iPS cells are expected to help pharmaceutical companies make use of their huge inventories of candidate substances.