title: Generation of a Nonhuman Primate Model of Severe Combined Immunodeficiency Using Highly Efficient Genome Editing.
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.
authors.affiliation: Central Institute for Experimental Animals, Kawasaki, Kanagawa 210-0821, Japan.
authors.forename: Kenya
authors.initials: K
authors.lastname: Sato
authors.affiliation: Central Institute for Experimental Animals, Kawasaki, Kanagawa 210-0821, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Oiwa
authors.affiliation: Central Institute for Experimental Animals, Kawasaki, Kanagawa 210-0821, Japan.
authors.forename: Wakako
authors.initials: W
authors.lastname: Kumita
authors.affiliation: Horizon Discovery, Saint Louis, MO 63146, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Henry
authors.affiliation: Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Hiroshima 739-8526, Japan.
authors.forename: Tetsushi
authors.initials: T
authors.lastname: Sakuma
authors.affiliation: Central Institute for Experimental Animals, Kawasaki, Kanagawa 210-0821, Japan.
authors.forename: Ryoji
authors.initials: R
authors.lastname: Ito
authors.affiliation: Central Institute for Experimental Animals, Kawasaki, Kanagawa 210-0821, Japan.
authors.forename: Ryoko
authors.initials: R
authors.lastname: Nozu
authors.affiliation: Central Institute for Experimental Animals, Kawasaki, Kanagawa 210-0821, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Inoue
authors.affiliation: Central Institute for Experimental Animals, Kawasaki, Kanagawa 210-0821, Japan.
authors.forename: Ikumi
authors.initials: I
authors.lastname: Katano
authors.affiliation: Department of Biosciences and Informatics, Keio University, Yokohama, Kanagawa 223-8522, Japan.
authors.forename: Kengo
authors.initials: K
authors.lastname: Sato
authors.affiliation: Central Institute for Experimental Animals, Kawasaki, Kanagawa 210-0821, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Okahara
authors.affiliation: Central Institute for Experimental Animals, Kawasaki, Kanagawa 210-0821, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Okahara
authors.affiliation: Central Institute for Experimental Animals, Kawasaki, Kanagawa 210-0821, Japan.
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Shimizu
authors.affiliation: Central Institute for Experimental Animals, Kawasaki, Kanagawa 210-0821, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Yamamoto
authors.affiliation: Department of Oncology, Juntendo University Nerima Hospital, Nerima-ku, Tokyo 177-8521, Japan.
authors.forename: Kisaburo
authors.initials: K
authors.lastname: Hanazawa
authors.affiliation: Medical Proteo Scope Company, Ltd., Yokohama, Kanagawa 236-0004, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Kawakami
authors.affiliation: Department of Molecular Life Science, Division of Basic Medical Science and Molecular Medicine, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan.
authors.forename: Yoshie
authors.initials: Y
authors.lastname: Kametani
authors.affiliation: Department of Rheumatology and Clinical Immunology, Clinical Research Center for Rheumatology and Allergy, Sagamihara National Hospital, Sagamihara, Kanagawa 252-0392, Japan.
authors.forename: Ryuji
authors.initials: R
authors.lastname: Suzuki
authors.affiliation: Central Institute for Experimental Animals, Kawasaki, Kanagawa 210-0821, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Takahashi
authors.affiliation: Horizon Discovery, Saint Louis, MO 63146, USA.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Weinstein
authors.affiliation: Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Hiroshima 739-8526, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: Department of Biosciences and Informatics, Keio University, Yokohama, Kanagawa 223-8522, Japan.
authors.forename: Yasubumi
authors.initials: Y
authors.lastname: Sakakibara
authors.affiliation: Atopy Research Center, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: Sonoko
authors.initials: S
authors.lastname: Habu
authors.affiliation: Central Institute for Experimental Animals, Kawasaki, Kanagawa 210-0821, Japan.
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Hata
authors.affiliation: Department of Physiology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan. Electronic address: hidokano@a2.keio.jp.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Okano
authors.affiliation: 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.
authors.forename: Erika
authors.initials: E
authors.lastname: Sasaki
mesh_terms: D000375:Aging / Q000473:pathology; D000818:Animals; D000831:Animals, Newborn; D001757:Blastomeres / Q000378:metabolism; D001947:Breeding; D002144:Callithrix; D004195:Disease Models, Animal; D004622:Embryo, Mammalian / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D018703:Founder Effect; D000072669:Gene Editing; D055786:Gene Knockout Techniques; D016678:Genome; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit / Q000378:metabolism; D008297:Male; D009030:Mosaicism; D010641:Phenotype; D015203:Reproducibility of Results; D016511:Severe Combined Immunodeficiency / Q000235:genetics* / Q000276:immunology / Q000469:parasitology; D013094:Spermatozoa / Q000378:metabolism; D000069896:Transcription Activator-Like Effector Nucleases / Q000378:metabolism; D016335:Zinc Fingers
chemical_list: D053631:Interleukin Receptor Common gamma Subunit; D000069896:Transcription Activator-Like Effector Nucleases