2006 Fiscal Year Final Research Report Summary
Gene therapy for chronic granulomatous disease in combination with selective cell amplification and utilizing hematopoietic microenvironment
| Project/Area Number |
16390306
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pediatrics
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| Research Institution | JICHI MEDICAL UNIVERSITY |
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Principal Investigator |
KUME Akihiro Jichi Medical University, School of Medicine, Associate Professor, 医学部, 助教授 (10264293)
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| Co-Investigator(Kenkyū-buntansha) |
OZAWA Keiya Jichi Medical University, School of Medicine, Professor, 医学部, 教授 (30137707)
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| Project Period (FY) |
2004 – 2006
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| Keywords | gene therapy / transplantation / chronic granulomatous disease / cell and tissue / translational research |
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| Research Abstract |
To improve the efficacy of hematopoietic stem cell gene therapy, selective amplifier genes (SAGs) were refined. SAGs are artificial genes encoding chimeric receptors comprising growth factor receptors and the extracellular domain of erythropoietin (Epo) receptor. Such fusion molecules generate growth signal when activated by Epo, and all the components were derived from human proteins. After confirming the fact that the refined SAGs functioned as cell growth switch in vitro, we chose the best SAG to further clarify its in vivo efficacy in the mouse model of X-linked chronic granulomatous disease (X-CGD). Bone marrow cells from donor X-CGD mice were transduced with a retrovirus vector carrying the SAG and the gp91-phox gene, the therapeutic gene for X-CGD, and transfused to X-CGD recipients. The first round Epo administration resulted in a significant increase of functionally corrected neutrophils in the recipients (from 1.0±0.1% to 3.9±0.8%; p=0.006), and the second round Epo administr
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ation lead brought up a similar increase (from 1.5±1.1% to 3.9±0.8%; p=0.065). The result demonstrated that the Epo-responsive SAG product reinforced the efficacy of stem cell gene therapy. Preclinical studies of the SAG system with non-human primates are to be launched.
The efficacy of intra-bone marrow transplantation (iBMT) was investigated in the X-CGD mouse model. This method allows very small number of hematopoietic stem cells to engraft otherwise rejected. Reduced intensity preconditioning is preferable in stem cell transplantation and gene therapy for X-CGD, to minimize procedure-associated risks. When more than 10^6 wild type bone marrow cells were transplanted through either intravenous infusion or iBMT, donor cells engrafted in X-CGD recipients given a low-dose irradiation (4 Gy). However only iBMT allowed wild type cells to engraft when the number of donor cells were smaller than 10^6.
Mesnchimal stem cells (MSCs) give rise to various lineages of cells including bone marrow stromal cells displaying the hematopoietic niche. We investigated the difference between MSC-like 10T1/2 cells and their preadipocyte-like derivative A54 cells. A54 cells overexpressed cytokines such as Steel factor, CXCL12 and Ang-1 which were further upregulated upon treatment of a myeloid cell-derived cytokine. In accordance with this upregulation, cobblestone and colony formation by cocultured hematopoietic stem/progenitor cells was augmented. The result suggested that cotransplantation of MSCs would support the engraftment of hematopoic stem cells. Less
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Research Products
(12 results)
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[Journal Article] Utility of intraperitoneal administration as a route of AAV serotype 5 vector-mediated neonatal gene transfer.2006
Author(s)
Ogura T, Mizukami H, Mimuro J, Okada T, Matsushita T, Urabe M, Kume A, Hamada H, Yoshikawa H, Sakata Y, Ozawa K
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Journal Title
J Gene Med 8(8)
Pages: 990-997
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Long-term correction of hyperphenylalaninemia by AAV-mediated gene transfer leads to behavioral recovery in phenylketonuria mice.2004
Author(s)
Mochizuki S, Mizukami H, Ogura T, Kure S, Ichinohe A, Kojima K, Matsubara Y, Kobayashi E, Okada T, Hoshika A, Ozawa K, Kume A
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Journal Title
Gene Ther 11(13)
Pages: 1081-1086
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] High-level in vivo gene marking after gene-modified autologous hematopoietic stem cell transplantation without marrow conditioning in nonhuman primates.2004
Author(s)
Ueda K, Hanazono Y, Shibata H, Ageyama N, Ueda Y, Ogata S, Tabata T, Nagashima T, Takatoku M, Kume A, Ikehara S, Taniwaki M, Terao K, Hasegawa M, Ozawa K
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Journal Title
Mol Ther 10(3)
Pages: 469-477
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Adeno-associated virus vector-mediated interleukin-1O gene transfer inhibits atherosclerosis in apoprotein E-deficient mice.2004
Author(s)
Yoshioka T, Okada T, Maeda Y, Ikeda U, Shimpo M, Nomoto T, Takeuchi K, Nonaska-Sarukawa M, Ito T, Takahashi T, Mizukami H, Hanazono Y, Kume A, Ookawara S, Kawano M, Ishibashi S, Shimada K, Ozawa K
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Journal Title
Gene Ther 11(24)
Pages: 1772-1779
Description
「研究成果報告書概要(欧文)」より
