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Cell Stem Cell. 2016 Jul 7;19(1):127-38. doi: 10.1016/j.stem.2016.06.003. Epub 2016 Jun 30.

Generation of a Nonhuman Primate Model of Severe Combined Immunodeficiency Using Highly Efficient Genome Editing.

Author information

1
Central Institute for Experimental Animals, Kawasaki, Kanagawa 210-0821, Japan.
2
Horizon Discovery, Saint Louis, MO 63146, USA.
3
Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Hiroshima 739-8526, Japan.
4
Department of Biosciences and Informatics, Keio University, Yokohama, Kanagawa 223-8522, Japan.
5
Department of Oncology, Juntendo University Nerima Hospital, Nerima-ku, Tokyo 177-8521, Japan.
6
Medical Proteo Scope Company, Ltd., Yokohama, Kanagawa 236-0004, Japan.
7
Department of Molecular Life Science, Division of Basic Medical Science and Molecular Medicine, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan.
8
Department of Rheumatology and Clinical Immunology, Clinical Research Center for Rheumatology and Allergy, Sagamihara National Hospital, Sagamihara, Kanagawa 252-0392, Japan.
9
Atopy Research Center, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan.
10
Department of Physiology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan. Electronic address: hidokano@a2.keio.jp.
11
Central Institute for Experimental Animals, Kawasaki, Kanagawa 210-0821, Japan; Advanced Research Center, Keio University, Shinjuku-ku, Tokyo 160-8582, Japan. Electronic address: esasaki@ciea.or.jp.

Abstract

Recent advances in genome editing have facilitated the generation of nonhuman primate (NHP) models, with potential to unmask the complex biology of human disease not revealed by rodent models. However, their broader use is hindered by the challenges associated with generation of adult NHP models as well as the cost of their production. Here, we describe the generation of a marmoset model of severe combined immunodeficiency (SCID). This study optimized zinc-finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs) to target interleukin-2 receptor subunit gamma (IL2RG) in pronuclear stage marmoset embryos. Nine of 21 neonates exhibited mutations in the IL2RG gene, concomitant with immunodeficiency, and three neonates have currently survived from 240 days to 1.8 years. Our approach demonstrates highly efficient production of founder NHP with SCID phenotypes, with promises of multiple pre-clinical and translational applications.

PMID:
27374787
DOI:
10.1016/j.stem.2016.06.003
[Indexed for MEDLINE]
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