HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hanazono, Y. Articles by Ozawa, K. Search for Related Content PubMed PubMed Citation Articles by Hanazono, Y. Articles by Ozawa, K.

Gene Transfer into Nonhuman Primate Hematopoietic Stem Cells: Implications for Gene Therapy

^a Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical School, Tochigi, Japan;
^b Tsukuba Primate Center, National Institute of Infectious Diseases, Ibaraki, Japan

Key Words. Gene therapy • Hematopoietic stem cells • Retroviral vectors • Nonhuman primate models

Yutaka Hanazono, M.D., Ph.D., Assistant Professor, Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical School, 3311-1 Yakushiji, Minamikawachi, Kawachi, Tochigi 329-0498, Japan. Telephone: 81-285-58-7402; Fax: 81-285-44-8675; e-mail: hanazono{at}jichi.ac.jp

Hematopoietic stem cells (HSCs) are desirable targets for gene therapy because of their self-renewal and multilineage differentiation abilities. Retroviral vectors are extensively used for HSC gene therapy. However, the initial human trials of HSC gene marking and therapy showed that the gene transfer efficiency into human HSCs with retroviral vectors was very low in contrast to the much higher efficiency observed in murine experiments. The more quiescent nature of human HSCs and the lower density of retroviral receptors on them hindered the efficient gene transfer with retroviral vectors. Since nonhuman primates have marked similarity to humans in all aspects including the HSC biology, their models are considered to be important to evaluate and improve gene transfer into human HSCs. Using these models, clinically relevant levels (around 10% or even more) of gene-modified cells in peripheral blood have recently been achieved after gene transfer into HSCs and their autologous transplantation. This has been made possible by improving ex vivo transduction conditions such as introduction of Flt-3 ligand and specific fibronectin fragment (CH-296) into ex vivo culture during transduction, and the use of retroviral vectors pseudotyped with the gibbon ape leukemia virus or feline endogenous retrovirus envelope. Other strategies including the use of lentiviral vectors and in vivo selective expansion of gene-modified cells with the drug resistance gene or selective amplifier gene (also designated the molecular growth switch) are now being tested to further increase the fraction of gene-modified cells using nonhuman primate models. In addition to the high gene transfer efficiency, high-level and long-term expression of transgenes in human HSCs and their progeny is also required for effective HSC gene therapy. For this purpose, other backbones of retroviral vectors such as the murine stem cell virus and cis-DNA elements, such as the ß-globin locus control region and the chromatin insulator, also need to be tested in nonhuman primate models. Nonhuman primate studies will continue to provide an important framework for human HSC gene therapy. Well-designed nonhuman primate studies will also offer unique insights into the HSCs, immune system, and transplantation biology characteristic of large animals.

This article has been cited by other articles:

				F. Ma, N. Kambe, D. Wang, G. Shinoda, H. Fujino, K. Umeda, A. Fujisawa, L. Ma, H. Suemori, N. Nakatsuji, et al. Direct Development of Functionally Mature Tryptase/Chymase Double-Positive Connective Tissue-Type Mast Cells from Primate Embryonic Stem Cells Stem Cells, March 1, 2008; 26(3): 706 - 714. [Abstract] [Full Text] [PDF]

				M. Hosseinkhani, H. Hosseinkhani, A. Khademhosseini, F. Bolland, H. Kobayashi, and S. P. Gonzalez Bone Morphogenetic Protein-4 Enhances Cardiomyocyte Differentiation of Cynomolgus Monkey ESCs in Knockout Serum Replacement Medium Stem Cells, March 1, 2007; 25(3): 571 - 580. [Abstract] [Full Text] [PDF]

				K. Umeda, T. Heike, M. Yoshimoto, G. Shinoda, M. Shiota, H. Suemori, H. Y. Luo, D. H. K. Chui, R. Torii, M. Shibuya, et al. Identification and Characterization of Hemoangiogenic Progenitors During Cynomolgus Monkey Embryonic Stem Cell Differentiation Stem Cells, May 1, 2006; 24(5): 1348 - 1358. [Abstract] [Full Text] [PDF]

				T. Yoshioka, N. Ageyama, H. Shibata, T. Yasu, Y. Misawa, K. Takeuchi, K. Matsui, K. Yamamoto, K. Terao, K. Shimada, et al. Repair of Infarcted Myocardium Mediated by Transplanted Bone Marrow-Derived CD34+ Stem Cells in a Nonhuman Primate Model Stem Cells, March 1, 2005; 23(3): 355 - 364. [Abstract] [Full Text] [PDF]