title: The common marmoset as a target preclinical primate model for cytokine and gene therapy studies.
abstract: Nonhuman primate models are useful to evaluate the safety and efficacy of new therapeutic modalities, including gene therapy, before the inititation of clinical trials in humans. With the aim of establishing safe and effective approaches to therapeutic gene transfer, we have been focusing on a small New World monkey, the common marmoset, as a target preclinical model. This animal is relatively inexpensive and easy to breed in limited space. First, we characterized marmoset blood and bone marrow progenitor cells (BMPCs) and showed that human cytokines were effective to maintain and stimulate in culture. We then examined their susceptibility to transduction by retroviral vectors. In a mixed culture system containing both marmoset stromal cells and retroviral producer cells, the transduction efficiency into BMPCs and peripheral blood progenitor cells (PBPCs) was 12% to 24%. A series of marmosets then underwent transplantation with autologous PBPCs transduced with a retroviral vector carrying the multidrug resistance 1 gene (MDR1) and were followed for the persistence of these cells in vivo. Proviral DNA was detectable by polymerase chain reaction (PCR) in peripheral blood granulocytes and lymphocytes in the recipients of gene transduced progenitors up to 400 days posttransplantation. To examine the function of the MDR1 gene in vivo, recipient maromsets were challenged with docetaxel, an MDR effluxed drug, yet the overall level of gene transfer attained in vivo (<1% in peripheral blood granulocytes) was not sufficient to prevent the neutropenia induced by docetaxel treatment. Using this model, we safely and easily performed a series of in vivo studies in our small animal center. Our results show that this small nonhuman primate, the common marmoset, is a useful model for the evaluation of gene transfer methods targeting hematopoietic stem cells.
authors.affiliation: Departments of Hematology/Oncology and Clinical Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Hibino
authors.forename: K
authors.initials: K
authors.lastname: Tani
authors.forename: K
authors.initials: K
authors.lastname: Ikebuchi
authors.forename: M S
authors.initials: MS
authors.lastname: Wu
authors.forename: H
authors.initials: H
authors.lastname: Sugiyama
authors.forename: Y
authors.initials: Y
authors.lastname: Nakazaki
authors.forename: T
authors.initials: T
authors.lastname: Tanabe
authors.forename: S
authors.initials: S
authors.lastname: Takahashi
authors.forename: A
authors.initials: A
authors.lastname: Tojo
authors.forename: S
authors.initials: S
authors.lastname: Suzuki
authors.forename: Y
authors.initials: Y
authors.lastname: Tanioka
authors.forename: Y
authors.initials: Y
authors.lastname: Sugimoto
authors.forename: T
authors.initials: T
authors.lastname: Nakahata
authors.forename: S
authors.initials: S
authors.lastname: Asano
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics*; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D002144:Callithrix; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology* / Q000627:therapeutic use; D004279:DNA, Viral / Q000032:analysis; D004195:Disease Models, Animal; D000077143:Docetaxel; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D006098:Granulocytes / Q000502:physiology / Q000821:virology; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008214:Lymphocytes / Q000502:physiology / Q000821:virology; D017239:Paclitaxel / Q000031:analogs & derivatives / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D012190:Retroviridae; D017154:Stromal Cells / Q000166:cytology; D043823:Taxoids; D014182:Transplantation, Autologous
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D016207:Cytokines; D004279:DNA, Viral; D043823:Taxoids; D016179:Granulocyte Colony-Stimulating Factor; D000077143:Docetaxel; D017239:Paclitaxel