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Blood, Vol. 93 No. 9 (May 1), 1999:
pp. 2839-2848
The Common Marmoset as a Target Preclinical Primate Model for
Cytokine and Gene Therapy Studies
Hitoshi Hibino,
Kenzaburo Tani,
Kenji Ikebuchi,
Ming-Shiuan Wu,
Hajime Sugiyama,
Yukoh Nakazaki,
Tsuyoshi Tanabe,
Satoshi Takahashi,
Arinobu Tojo,
Shuzo Suzuki,
Yoshikuni Tanioka,
Yoshikazu Sugimoto,
Tatsutoshi Nakahata, and
Shigetaka Asano
From the Departments of Hematology/Oncology and Clinical Oncology,
The Institute of Medical Science, The University of Tokyo, Tokyo; the
Research Department, Hokkaido Red Cross Blood Center, Sapporo; the
Central Institute for Experimental Animals, Kawasaki; the Cancer
Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo;
Japan.
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.
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