Proposal forcollaborative research using unique genetically modified non-human primates
Shiga University of Medical Science (SUMS) is recruiting new research collaboration using
genetically modified non-human primates (NHP) from around the world. We are highly expecting
collaborative research with universities abroad, and are introducing facility and researchers.

About RCALSSUMS have Research Center for Animal Life Science (RCALS) which is the joint-use facility for animal
experimentation performed in accordance with international regulations. RCALS is mainly focused on
generating and using NHP as model animal for human diseases. There are about 700 cynomolgusmonkeys (Macaca fascicularis) in RCALS which is the largest NHP facility in Japan.
RCALS has two unique techniques for artificial breeding and genetic transformation to generate M.
fascicularis. RCALS have generated M. fascicularis such as:
1. M. fascicularis with homozygous Major Histocompatibility Complex (MHC) haplotype which isuseful in the research field of regenerative medicine using iPS cell.
2. M. fascicularis model of some diseases including dementia and some unpublished diseases.
RCALS is now the satellite of the Institute for Advanced Synthesis of Human Biology (ASHBi), Kyoto
University which is funding from the MEXT provided under its FY2018 World Premier International
Research Center Initiative (WPI) program.
As you may know, exporting gene modified M. fascicularis to US is very hard by the Convention on
Biological Diversity (CBD), Access to genetic resources and Benefit Sharing (ABS), etc. So it is better for
researchers of universities abroad to visit to SUMS to carry out collaborative research.

Contact
Academia-Industry Collaboration Section, Research Strategy Promotion Office,Research Administration Office,Shiga University of Medical Science
Seta Tsukinowa-cho, Otsu, Shiga 520-2192, JAPANTel: +81-77-548-2936
E-mail: sangaku[a]belle.shiga-med.ac.jp (Replace [a] to @ when sending email)1/5

Researchers in Medical Research using Cynomolgus Monkeys
Kazumasa Ogasawara (Professor, Div. Pathology and Disease Regulation, Director of Academic Affairs
and Research and Vice President of SUMS)
Research Interest:
He is interested in establishment of disease models of cynomolgus monkeys for preclinical studies.
Mice are used as disease models, but all mice disease models do not reproduced human disease. Thus,
he focuses on establishment of disease models in none but cynomolgus monkeys. In addition, he isinterested in transplantation using cynomolgus monkeys, which are identified for major
histocompatibility complex (MHC). Indeed, the MHC-identified cynomolgus monkeys were used in thetransplantation experiments of differentiated iPS cells, such as neurons, retinal pigment epithelial cells
and cardiomyocytes.
Articles:
1. Sugita S, Iwasaki Y, Makabe K, Kamao H, Mandai M, Shiina T, Ogasawara K, Hirami Y, Kurimoto Y,Takahashi M. Successful Transplantation of Retinal Pigment Epithelial Cells from MHC
Homozygote iPSCs in MHC-Matched Models. Stem Cell Reports 7(4), 635-648 (2016), doi:10.1016/j.stemcr.2016.08.010
2.

Kawamura, T, Miyagawa S, fukushima S, Maeda A, Kashiyama N, Kawamura A, Miki K, Okita K,Yoshida Y, Shiina T, Ogasawara K, Miyagawa S, Toda K, Okuyama H, Sawa Y. Cardiomyocytes
derived from MHC-homozygous induced pluripotent stem cells exhibit reduce allogeneic
immunogenicity in MHC-matched non-human primates. Stem Cell Reports 6(3), 312-320 (2016),
doi: 10.1016/j.stemcr.2016.01.012

3.

Morizane A, Kikuchi T, Hayashi T, Mizuma H, Takara S, Doi H, Mawatari A, Glasser MF, Shiina T,Ishigaki H, Itoh Y, Okita K, Yamasaki E, Doi D, Onoe H, Ogasawara K, Yamanaka S, Takahashi J. MHC
matching improves engraftment of iPSC-derived neurons in non-human primates. Nat Commun8(1), 385 (2017), doi: 10.1038/s41467-017-00926-5

4.

Ishigaki H, Maeda T, Inoue H, Akagi T, Sasamura T, Ishida H, Inubushi T, Okahara J, Shiina T,Nakayama M, Itoh Y, Ogasawara K. Transplantation of iPS-derived tumor cells with ahomozygous MHC haplotype induces GRP94 antibody production in MHC-matched macaques.
Cancer Res 77(21), 1-10 (2017), doi: 10.1158/0008-5472.CAN-17-0775

5.

Ishigaki H, Shiina T, Ogasawara K. MHC-identical and transgenic cynomolgus macaques forpreclinical studies. Inflamm Regen 38, 30 (2018), doi: 10.1186/s41232-018-0088-3

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Yasushi Itoh (Associate professor, Div. Pathology and Disease Regulation)
Research Interest:
He has been developed two disease models using cynomolgus monkeys: influenza and prematureaging. Various influenza viruses including seasonal and highly pathogenic avian influenza viruses causeclinical signs of diseases in macaques as seen in humans. The premature aging model of genome-edited
macaques is expected to show age-related metabolic disorders and tumors. Since macaques’ immunity
and metabolism are similar to humans’, the macaque model is suitable to evaluate the efficacy ofvaccines and drugs as preclinical studies.
Articles:
1. Itoh Y, Shinya K, Kiso M, Watanabe T, Sakoda Y, Hatta M, Muramoto Y, Tamura D, Sakai-Tagawa Y,Noda T, Sakabe S, Imai M, Hatta Y, Watanabe S, Li C, Yamada S, Fujii K, Murakami S, Imai H,Kakugawa S, Ito M, Takano R, Iwatsuki-Horimoto K, Shimojima M, Horimoto T, Goto H, Takahashi K,Makino A, Ishigaki H, Nakayama M, Okamatsu M, Takahashi K, Warshauer D, Shult PA, Saito R,Suzuki H, Furuta Y, Yamashita M, Mitamura K, Nakano K, Nakamura M, Brockman-Schneider R,Mitamura H, Yamazaki M, Sugaya N, Suresh M, Ozawa M, Neumann G, Gern J, Kida H, Ogasawara
K, Kawaoka Y. In vitro and in vivo characterization of new swine-origin H1N1 influenza viruses.
Nature 460, 1021-1025 (2009), doi: 10.1038/nature08260
2. Kitano M, Itoh Y, Ishigaki H, Nakayama M, Ishida H, Pham VL, Arikata M, Shichinohe S, Tsuchiya H,Kitagawa N, Kobayashi M, Yoshida R, Sato A, Le QM, Kawaoka Y, Ogasawara K. Efficacy of repeatedintravenous administration of peramivir against highly pathogenic avian influenza A (H5N1) virus
in cynomolgus macaques. Antimicrob Agents Chemother 58(8), 4795-4803 (2014), doi:
10.1128/AAC.02817-14
3. Itoh Y, Yoshida R, Shichinohe S, Higuchi M, Ishigaki H, Nakayama M, Pham VL, Ishida H, Kitano M,Arikata M, Kitagawa N, Mitsuishi Y, Ogasawara K, Tsuchiya H, Hiono T, Okamatsu M, Sakoda Y, Kida
H, Ito M, Le QM, Kawaoka Y, Miyamoto H, Ishijima M, Igarashi M, Suzuki Y, Takada A. Protective
efficacy of passive immunization with monoclonal antibodies in animal models of H5N1 highly
pathogenic avian influenza virus infection. PLoS Pathog 10(6), e1004192 (2014), doi:10.1371/journal.ppat.1004192
4. Itoh Y, Shichinohe S, Nakayama M, Igarashi M, Ishii A, Ishigaki H, Ishida H, Kitagawa N, Sasamura T,Shiohara M, Doi M, Tsuchiya H, Nakamura S, Okamatsu M, Sakoda Y, Kida H, Ogasawara K.
Emergence of H7N9 influenza A virus resistant to neuraminidase inhibitors in nonhuman primates.
Antimicrob Agents Chemother 59(8), 4962-4973 (2015), doi: 10.1128/AAC.00793-15
5. Morizane A, Kikuchi T, Hayashi T, Mizuma H, Takara S, Doi H, Mawatari A, Glasser MF, Shiina T,Ishigaki H, Itoh Y, Okita K, Yamasaki E, Doi D, Onoe H, Ogasawara K, Yamanaka S, Takahashi J. MHC
matching improves engraftment of iPSC-derived neurons in non-human primates. Nat Commun
8(1), 385 (2017), doi: 10.1038/s41467-017-00926-5

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Masatsugu Ema (Professor, Dept. Stem Cells and Human Disease Models, Director of RCALS)
Research Interest:
Nonhuman primates (NHPs) are considered one of the most valuable animal models, because NHPs
are closer to humans in organ size and anatomical structure. So far, he has established techniques tocreate transgenic and genome editing cynomolgus monkeys. By using these techniques, he has
explored an intractable human disease, Autosomal dominant polycystic kidney disease (ADPKD) withCRISPR/Cas9 technique, and demonstrated that targeted disruption of PKD1, a causative gene for
ADPKD can recapitulate the human ADPKD pathology. He believes that disease modeling withgenetically modified-cynomolgus monkey will open the way for the elucidation of molecularmechanism of human diseases and new therapeutic approaches.
Articles:
1. Seita Y, Tsukiyama T, Azami T, Kobayashi K, Iwatani C, Tsuchiya H, Nakaya M, Tanabe H, Hitoshi S,Miyoshi H, Nakamura S, Kawauchi A, Ema M, Comprehensive evaluation of ubiquitous promoterssuitable for the generation of transgenic cynomolgus monkeys. Biol Reprod. ioz040 (2019), doi:
10.1093/biolre/ioz040
2. Seita Y, Iwatani C, Tsuchiya H, Nakamura S, Kimura F, Murakami T, Ema M, Poor second ovarian
stimulation in cynomolgus monkeys (Macaca fascicularis) is associated with the production ofantibodies against human follicle-stimulating hormone. J Reprod Dev, Mar 7 (2019), doi:
10.1262/jrd.2018-156
3. Azami T, Waku T, Matsumoto K, Jeon H, Muratani M, Kawashima A, Yanagisawa J, Manabe I, Nagai
R, Kunath T, Nakamura T, Kurimoto K, Saitou M, Takahashi S, Ema M, Klf5 maintains the balanceof primitive endoderm versus epiblast specification during mouse embryonic development bysuppression of Fgf4. Development 144(20), 3706-3718 (2017), doi: 10.1242/dev.150755
4. Seita Y, Tsukiyama T, Iwatani C, Tsuchiya H, Matsushita J, Azami T, Okahara J, Nakamura S, Hayashi
Y, Hitoshi S, Itoh Y, Imamura T, Nishimura M, Tooyama I, Miyoshi H, Saitou M, Ogasawara K, Sasaki
E, Ema M, Generation of transgenic cynomolgus monkeys that express green fluorescent protein
throughout the whole body. Sci Rep. 6, 24868 (2016), doi: 10.1038/srep24868

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Ikuo Tooyama (Professor, Dept. Diagnostics and Therapeutics for Brain Diseases, Director of Molecular
Neuroscience Research Center (MNRC))
Research Interest:
He is interested in Alzheimer’s disease (AD) and related disorders. His research team have developed
several novel ligands for amyloid imaging or tau-imaging using 19F-MRI, such as Shiga-X and Shiga-Y.
Using these chemicals he has succeeded in amyloid and tau imaging in the brain of transgenic mousemodels such as Tg2576, APP/PS1 and rTg4510. Some of them have therapeutic potentials in transgenic
mouse models of AD. However, it is well known that these rodent models do not show the sameneuropathology as human Alzheimer's disease. Thus, he has collaborated with Professor Ema in RCALS
and developed monkey models over-expressing mutant APP gene. These monkey models should
provide us valuable tools to evaluate diagnostic and/or therapeutic effects as well as toxicity ofchemicals targeting AD.
Articles:
1. Yanagisawa D, Ibrahim NF, Taguchi H, Morikawa S, Kato T, Hirao K, Shirai N, Sogabe T, Tooyama I.
Fluorine-19 magnetic resonance imaging probe for the detection of tau pathology in female
rTg4510 mice. J Neurosci Res 96(5), 841-851 (2018), doi: 10.1002/jnr.24188
2. Tooyama I, Yanagisawa D, Taguchi H, Kato T, Hirao K, Shirai N, Sogabe T, Ibrahim NF, Inubushi T,Morikawa S. Amyloid imaging using fluorine-19 magnetic resonance imaging (19F-MRI). Ageing Res
Rev 30, 85-94 (2016), doi: 10.1016/j.arr.2015.12.008
3. Yanagisawa D, Ibrahim NF, Taguchi H, Morikawa S, Hirao K, Shirai N, Sogabe T, Tooyama I. Curcumin
derivative with the substitution at C-4 position, but not curcumin, is effective against amyloid
pathology in APP/PS1 mice. Neurobiol Aging 36(1), 201-210 (2015), doi:10.1016/j.neurobiolaging.2014.07.041
4. Yanagisawa D, Taguchi H, Ibrahim NF, Morikawa S, Shiino A, Inubushi T, Hirao K, Shirai N, Sogabe T,Tooyama I. Preferred features of a fluorine-19 MRI probe for amyloid detection in the brain. J
Alzheimer’s Dis 39(3), 617-631 (2014), doi: 10.3233/JAD-131025
5. Yanagisawa D, Amatsubo T, Morikawa S, Taguchi H, Urushitania M, Shirai N, Hirao K, Shiino A,Inubushid T, Tooyama I. In vivo detection of amyloid β deposition using 19F magnetic resonanceimaging with a 19F-containing curcumin derivative in a mouse model of Alzheimer’s disease.
Neuroscience 184, 120-127 (2011), doi: 10.1016/j.neuroscience.2011.03.071

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