IMPROVED GENE TRANSDUCTION WITH RECOMBINANT AAV FOLLOWING IMMUNE TOLERANCE.
| Project/Area Number |
16K07081
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Laboratory animal science
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| Research Institution | University of Tsukuba |
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Principal Investigator |
Ishii Akiko 筑波大学, 医学医療系, 講師 (10400681)
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| Co-Investigator(Kenkyū-buntansha) |
喜納 裕美 (早下裕美) 日本医科大学, 大学院医学研究科, 助教 (60532728)
岡田 浩典 日本医科大学, 大学院医学研究科, 研究生 (80416271)
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| Research Collaborator |
Okada Takashi
Takeda Sin'ichi
Sankai Tadashi
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | 遺伝子治療 / 免疫寛容 / 筋ジストロフィー / アデノ随伴ウイルス / カニクイザル / ヒト歯髄類似細胞 / ＡＡＶベクター / 免疫寛容誘導 / 組換えＡＡＶ / 骨格筋 / 組換えAAVベクター / 歯髄類似細胞 / アデノ関連ウイルス |
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| Outline of Final Research Achievements |
Recombinant adeno-associated virus (rAAV) is a promising viral vector for gene therapy of Duchenne muscular dystrophy (DMD). Emergence of circulating dystrophin-specific T cells was reported in DMD patients treated with rAAV. Therefore, immunomodulation is a necessary requirement for successful gene therapy. Immune tolerance induction is immunosuppressive method and we used it as a novel alternative for this purpose. Our research consist on inducing immune tolerance using dental pulp stem cells (DPSCs) and the effects on the AAV-mediated expression of LacZ in the skeletal muscle of cynomolgus monkey. Without DPSCs, LacZ expression was not detected at any point of the observation period. Using DPSCs, LacZ expression was successfully detected at 48 weeks after the injection.
DPSCs administration was able to reduce immune response to rAAV9 and LacZ. This DPSCs-assisted transduction strategy can enhance the therapeutic benefits of AAV-mediated gene therapy of DMD.
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| Academic Significance and Societal Importance of the Research Achievements |
Duchenne型筋ジストロフィーは，根本的な治療法がなく，遺伝子治療法の確立が望まれている．本研究は組換えAAVが筋ジストロフィーの遺伝子治療に用いることができるかどうかを検討する研究であり，ヒトの遺伝子治療の基礎的研究として重要である．iPS細胞を使用しても，何らかの方法により効率的に欠失している遺伝子の導入が必要である．AAVは病原性がないこと，長期発現が可能であることからもっとも有望な遺伝子導入法である．本研究で組換えAAVの安全性および免疫寛容の誘導による効果の持続法が確立されれば，他の遺伝性疾患に対する遺伝子治療も選択肢が広がり，遺伝子疾患患者にとって福音であり社会的意義は大きい．
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Report
(4 results)
Research Products
(6 results)
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[Journal Article] Highly Efficient Ultracentrifugation-free Chromatographic Purification of Recombinant AAV Serotype 92018
Author(s)
Tomono Ｔ, Hirai Y, Okada H, Miyagawa Y, Adachi 1, Sakamoto S, Kawano Y, Chono H, Mineno J, Ishii A, Shimada T, Onodera M, Tamaoka A, Okada T.
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Journal Title
Mol Ther Methods Clin Dev
Volume: １１
Pages: 180-190
DOI
NAID
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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