2007 Fiscal Year Final Research Report Summary
Development of a new therapy of severe ichthyosis caused by ABCA12 mutations
| Project/Area Number |
18390310
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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 |
Dermatology
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| Research Institution | Hokkaido University |
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Principal Investigator |
MASASHI Akiyama Hokkaido University, Graduate School of Medicine, Associate Professor (60222551)
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| Co-Investigator(Kenkyū-buntansha) |
HIROSHI Shimizu Hokkaido University, Graduate School of Medicine, Professor (00146672)
NISHIE Wataru Hokkaido University, Graduate School of Medicine, Assi. Prof (20443955)
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| Project Period (FY) |
2006 – 2007
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| Keywords | ichthyosis / ABCA12 / gene therapy / mutation / harlequin ichthyosis / skin barrier / 皮膚バリア |
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| Research Abstract |
Serious defects in the epidermal keratinocyte lipid transporter ABCA12 are known to result in a deficient skin lipid barrier, leading to severe ichthyosis. In this study, we intended to develop a gene therapy method of severe icththyosis by an ABCA12 corrective gene transfer system for hair follicle epithelial stem cells. For persistent and stable transgene expression in hair follicle stem cells, we transferred retroviral vectors encoding reporter genes into cultured hair follicle stem cells. We performed gene transfection experiments into the bulge stem cells in vitro. We dissected bulge areas from mice vibrissa hair follicles and established primary cultures. The ABCA12 transfected cells were mixed with cultured dermal papilla cells and transplanted on to immunodeficient mice. We succeeded in reconstituting hair follciles and their appendages from the cells harboring a transgene reporter. The transgene expression was observed in all skin epithelial compartments including the hair follicle epithelium, sebaceous gland and epidermis. In addition, we performed gene transfection experiments into the bulge stem cells in vivo using the methods that had been established from in vitro studies.
Furthermore, we performed transfection experiments of gene constructs for gene therapy. In detail, we cloned normal ABCA12 cDNA construct with the transfection vector and the reporter genes selected from the results of previous experiments. We obtained keratinocyte cultures form severe ichthyosis patients harboring ABCA12 mutations after fully informed consents. Epidermis showing characteristic ichthyosis phenotype was reconstituted from these cultured keratinocytes form the patients on the back of nude mice. Targetting the reconstructed ichthyosis skin lesions, we tried gene therapy experiments using normal ABCA12 gene constructs. This hair follicle stem cell targeted ABCA12 corrective gene transfer system provided reliable gene therapy.
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Research Products
(6 results)
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[Journal Article] Unique mutations in the filaggrin gene in Japanese patients with ichthyosis vulgaris and atopic dermatitis2007
Author(s)
Nomura T, Sandilands A, Akiyama M, Sakai K, Ota M, Sugiura H, Yamamoto K, Sato H, Smith FJD, McLean WHI, Shimizu H.
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Journal Title
J Allergy Clin Immunol 119
Pages: 434-440
Description
「研究成果報告書概要(和文)」より
Peer Reviewed
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[Journal Article] J Allergy Clin Immunol2007
Author(s)
Nomura T, Sandilands A, Akiyama M, Sakai K, Ota M, Sugiura H, Yamamoto K, Sato H, Smith FJD, McLean WHI, Shimizu H.
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Journal Title
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Am J Pathol2007
Author(s)
Yamanaka Y, Akiyama M, Sugiyama-Nakagiri Y, Sakai K, Goto M, McMillan JR, Ota M, Sawamura D, Shimizu H
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Journal Title
Description
「研究成果報告書概要(欧文)」より
