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August 31, 2017

Curing Parkinson's disease is not for monkey brains

CiRA researchers show that matching donors and recipients reduces the immune rejection of induced pluripotent stem (iPS) cell-derived neurons for treatment of Parkinson's disease in monkeys. The finding will be a basis to treat human patients.

It may surprise the average person to know that a cure for Parkinson's disease may have been found decades ago. Many Parkinson's disease patients have benefited from the transplantation of dopamine neurons, which are the neurons destroyed in their brains by the disease. Two reasons have prevented this treatment from becoming standard. One is finding dopamine neurons for the transplantation, and two is the poor survival of the grafted cells in part because of the patient's immune system rejecting the transplant. A new study by CiRA researchers shows that these problems can be solved by using iPS cells, at least in monkey. The study can be read in Nature Communications.

"Dopamine neurons made from fetal tissue have been used to treat Parkinson's disease. We cannot standardize the dopamine neurons because fetal tissue is hard to acquire," says Neurosurgeon and CiRA Assistant Professor Asuka Morizane, who first-authored the study.

Due to poor standardization, the transplantation of neurons made from fetal tissue has shown success in only some patients. In other patients, the immune system reacts to and kills the transplanted cells.

Morizane has been leading a project in Prof. Jun Takahashi's lab that uses iPS cells to produce the dopamine neurons. Because iPS cells can be prepared from blood, they can be produced at ample numbers for standardization.

"In any transplantation, we treat the patient with immunosuppressants to prevent rejection. But immune suppression makes the patient susceptible to infection," adds Morizane.

For a transplantation to succeed, the donor and patient must have matching human leukocyte antigens (HLA) to prevent tissue rejection. The equivalent to HLA in monkeys is MHC, or major histocompatibility complex.

The researchers found that dopamine neurons derived from MHC-matched monkey iPS cells stimulated far less neuroinflammation when transplanted into monkey brains than did dopamine neurons derived from MHC-unmatched monkey iPS cells. While this difference did not completely eliminate the need for immunosuppressants, it did lower the dosage so as to reduce the risk of infection. The effects were confirmed at 4 months after the transplantation, which is considered long enough to judge the immune tolerance.

Morizane says that these findings will contribute to the design of the first iPS cell-based therapy for Parkinson's disease.

"We concluded that the combination of MHC-matching and immunosuppression will reduce the dose and duration of the immunosuppresive drug and be the best strategy for the transplantation."

The Takahashi lab is hopeful that it will begin patient recruitment for an experimental therapy by the end of next year.

Paper Details
  • Journal: Nature Communications
  • Title: MHC matching improves engraftment of iPSC-derived neurons in non-human primates
  • Authors: Asuka Morizane1, Tetsuhiro Kikuchi1, Takuya Hayashi2, Hiroshi Mizuma2, Sayuki Takara2, Hisashi Doi2, Aya Mawatari2, Matthew F. Glasser3, Takashi Shiina4, Hirohito Ishigaki5, Yasushi Itoh5, Keisuke Okita1, Emi Yamasaki1, Daisuke Doi1, Hirotaka Onoe2, Kazumasa Ogasawara5, Shinya Yamanaka1,6, and Jun Takahashi1,7*

    *corresponding author
  • Author Affiliations:
    1. Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan
    2. RIKEN Center for Life Science and Technologies (CLST), Kobe, Japan
    3. Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, USA
    4. Department of Basic Medical Science and Molecular Medicine, Tokai University, Kanagawa, Japan
    5. Department of Pathology, Shiga University of Medical Science, Shiga, Japan
    6. Gladstone Institute of Cardiovascular Disease, San Francisco, CA, USA
    7. Department of Neurosurgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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