Development of a technique that allows repeatable gene transfer into the brain using AAV vectors
Project/Area Number |
19K06899
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Multi-year Fund |
Section | 一般 |
Review Section |
Basic Section 46010:Neuroscience-general-related
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Research Institution | Gunma University |
Principal Investigator |
Konno Ayumu 群馬大学, 大学院医学系研究科, 講師 (40509048)
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Co-Investigator(Kenkyū-buntansha) |
渡邉 康春 富山県薬事総合研究開発センター, その他部局等, 主任研究員 (80646307)
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Project Period (FY) |
2019-04-01 – 2023-03-31
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Project Status |
Completed (Fiscal Year 2022)
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Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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Keywords | 遺伝子治療 / アデノ随伴ウイルスベクター / AAVベクター / 血液脳関門 / 中和抗体 / AAV2-BR1N / ウイルスベクター |
Outline of Research at the Start |
アデノ随伴ウイルスベクターPHP.B(AAV-PHP.B; 以下PHP.Bと表記)は、血液脳関門を高効率に透過できるウイルスベクターであり、静脈内投与(静注)により、週齢を問わずマウスの脳全域への遺伝子導入が可能である。ごく最近、研究代表者は、PHP.Bを静注した個体血中において、速やかに中和抗体が産生され、二度目以降の静注による遺伝子導入が完全に阻害されることを報告した。脳全域への遺伝子導入が一度しか行えない事実は、PHP.Bの応用性を限定的なものにしている。このため本研究では、期間を空けてPHP.Bを繰り返し静注しても、脳全域への遺伝子導入が何度でも可能となる技術を確立することを目指す。
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Outline of Final Research Achievements |
Adeno-associated virus (AAV)-PHP.B, a capsid variant of AAV serotype 9 (AAV9), is highly permeable to the blood-brain barrier (BBB) of mice, and can deliver genes to the brain with high efficiency by intravenous administration. However, because neutralizing antibodies are produced in individuals once PHP.B has been administered, gene transfer by a second intravenous administration are not possible. In this study, we developed a new BBB-transducing vector, BR1N, based on a different type of AAV (AAV2) that does not cross neutralizing antibodies with PHP.B. Using this vector, gene transfer to the brain by intravenous administration was possible even in individuals which had received PHP.B. We reported a research paper containing these results in Molecular Therapy - Methods & Clinical Development.
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Academic Significance and Societal Importance of the Research Achievements |
本研究で開発したBR1NはAAV血清型2(AAV2)を元にしたBBB透過型AAVベクターである。現在、多くの研究者がBBB透過型AAVベクターを開発しているが、その元になっているのはAAV9である。AAV9は他の血清型に比べて、高いBBB透過能を持つ事が知られていたのがその要因である。一方本研究では、これまでBBB透過能が知られていなかったAAV2を元にして作製した変異体が、マウスBBBの透過能を示す事を明らかにした。このことは、AAVベクターのカプシド開発に新たな道を開くものであると考えている。
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Report
(5 results)
Research Products
(46 results)
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[Journal Article] DOPAnization of tyrosine in α-synuclein by tyrosine hydroxylase leads to the formation of oligomers.2022
Author(s)
1.Jin M., Matsumoto S., Ayaki T., Yamakado H., Taguchi T., Togawa N., Konno A., Hirai H., Nakajima H., Komai S., Ishida R., Chiba S., Takahashi R., Takao T. and Hirotsune S.
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Journal Title
Nature Communications
Volume: 13(1):6880
Issue: 1
Pages: 6880-6880
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Protein kinase Cγ in cerebellar Purkinje cells regulates Ca 2+-activated large-conductance K + channels and motor coordination2022
Author(s)
Watanave M, Takahashi N, Hosoi N, Konno A, Yamamoto H, Yasui H, Kawachi M, Horii T, Matsuzaki Y, Hatada I, Hirai H.
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Journal Title
Proc Natl Acad Sci U S A
Volume: 119(7)
Issue: 7
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Urinary <scp>FABP1</scp> is a biomarker for impaired proximal tubular protein reabsorption and is synergistically enhanced by concurrent liver injury2021
Author(s)
Kawakami Ryo, Matsui Miki, Konno Ayumu, Kaneko Ryosuke, Shrestha Suman, Sunaga Hiroaki, Hanaoka Hirofumi, Goto Sawako, Hosojima Michihiro, Kabasawa Hideyuki, Obokata Masaru, Koitabashi Norimichi, Matsui Hiroki, Sasaki Tsutomu, Saito Akihiko, Yanagita Motoko, Hirai Hirokazu, Kurabayashi Masahiko, Iso Tatsuya
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Journal Title
The Journal of Pathology
Volume: 255
Issue: 4
Pages: 362-373
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] The Ser19Stop single nucleotide polymorphism (SNP) of human PHYHIPL affects the cerebellum in mice.2021
Author(s)
Hisako Sugimoto, Takuro Horii, Jun-Na Hirota, Yoshitake Sano, Yo Shinoda, Ayumu Konno, Hirokazu Hirai, Yasuki Ishizaki, Hajime Hirase, Izuho Hatada, Teiichi Furuichi, Tetsushi Sadakata.
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Journal Title
Molecular Brain
Volume: 52
Issue: 1
Pages: 1-9
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Deletion of Class II ADP-Ribosylation Factors in Mice Causes Tremor by the Nav1.6 Loss in Cerebellar Purkinje Cell Axon Initial Segments.2019
Author(s)
Hosoi N, Shibasaki K, Hosono M, Konno A, Shinoda Y, Kiyonari H, Inoue K, Muramatsu SI, Ishizaki Y, Hirai H, Furuichi T, Sadakata T
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Journal Title
J Neurosci
Volume: 39(32)
Issue: 32
Pages: 6339-6353
DOI
Related Report
Peer Reviewed
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