Delivery of Full-Length Factor VIII Using a piggyBac Transposon Vector to Correct a Mouse Model of Hemophilia A
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{"title"=>"Delivery of full-length factor VIII using a piggyBac transposon vector to correct a mouse model of hemophilia A", "type"=>"journal", "authors"=>[{"first_name"=>"Hideto", "last_name"=>"Matsui", "scopus_author_id"=>"7401527356"}, {"first_name"=>"Naoko", "last_name"=>"Fujimoto", "scopus_author_id"=>"56478325400"}, {"first_name"=>"Noriko", "last_name"=>"Sasakawa", "scopus_author_id"=>"14627764700"}, {"first_name"=>"Yasuhide", "last_name"=>"Ohinata", "scopus_author_id"=>"10143214200"}, {"first_name"=>"Midori", "last_name"=>"Shima", "scopus_author_id"=>"55366649400"}, {"first_name"=>"Shinya", "last_name"=>"Yamanaka", "scopus_author_id"=>"7202123309"}, {"first_name"=>"Mitsuhiko", "last_name"=>"Sugimoto", "scopus_author_id"=>"56804336500"}, {"first_name"=>"Akitsu", "last_name"=>"Hotta", "scopus_author_id"=>"22134741000"}], "year"=>2014, "source"=>"PLoS ONE", "identifiers"=>{"pui"=>"373772110", "issn"=>"19326203", "isbn"=>"1932-6203", "doi"=>"10.1371/journal.pone.0104957", "scopus"=>"2-s2.0-84920853211", "pmid"=>"25126862", "sgr"=>"84920853211"}, "id"=>"91bc6a29-c66a-37f1-9c1c-c052aee4ec67", "abstract"=>"Viral vectors have been used for hemophilia A gene therapy. However, due to its large size, full-length Factor VIII (FVIII) cDNA has not been successfully delivered using conventional viral vectors. Moreover, viral vectors may pose safety risks, e.g., adverse immunological reactions or virus-mediated cytotoxicity. Here, we took advantages of the non-viral vector gene delivery system based on piggyBac DNA transposon to transfer the full-length FVIII cDNA, for the purpose of treating hemophilia A. We tested the efficiency of this new vector system in human 293T cells and iPS cells, and confirmed the expression of the full-length FVIII in culture media using activity-sensitive coagulation assays. Hydrodynamic injection of the piggyBac vectors into hemophilia A mice temporally treated with an immunosuppressant resulted in stable production of circulating FVIII for over 300 days without development of anti-FVIII antibodies. Furthermore, tail-clip assay revealed significant improvement of blood coagulation time in the treated mice. piggyBac transposon vectors can facilitate the long-term expression of therapeutic transgenes in vitro and in vivo. This novel gene transfer strategy should provide safe and efficient delivery of FVIII.", "link"=>"http://www.mendeley.com/research/delivery-fulllength-factor-viii-using-piggybac-transposon-vector-correct-mouse-model-hemophilia", "reader_count"=>52, "reader_count_by_academic_status"=>{"Unspecified"=>3, "Professor > Associate Professor"=>2, "Librarian"=>1, "Student > Doctoral Student"=>3, "Researcher"=>13, "Student > Ph. D. Student"=>8, "Student > Postgraduate"=>7, "Student > Master"=>5, "Other"=>2, "Student > Bachelor"=>5, "Professor"=>3}, "reader_count_by_user_role"=>{"Unspecified"=>3, "Professor > Associate Professor"=>2, "Librarian"=>1, "Student > Doctoral Student"=>3, "Researcher"=>13, "Student > Ph. D. Student"=>8, "Student > Postgraduate"=>7, "Student > Master"=>5, "Other"=>2, "Student > Bachelor"=>5, "Professor"=>3}, "reader_count_by_subject_area"=>{"Unspecified"=>6, "Engineering"=>1, "Biochemistry, Genetics and Molecular Biology"=>14, "Medicine and Dentistry"=>7, "Agricultural and Biological Sciences"=>18, "Philosophy"=>1, "Neuroscience"=>1, "Chemistry"=>3, "Economics, Econometrics and Finance"=>1}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>1}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>7}, "Neuroscience"=>{"Neuroscience"=>1}, "Chemistry"=>{"Chemistry"=>3}, "Economics, Econometrics and Finance"=>{"Economics, Econometrics and Finance"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>18}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>14}, "Unspecified"=>{"Unspecified"=>6}, "Philosophy"=>{"Philosophy"=>1}}, "reader_count_by_country"=>{"United States"=>1}, "group_count"=>1}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1638577"], "description"=>"<p>(A) Bleeding time of both hemophilia A mice (n = 6) and hemophilia A mice treated with <i>piggyBac</i> vector expressing full-length Factor VIII (n = 5) assessed by tail-clip assay. (B) Immunohistochemical analysis of liver tissue from non-treated hemophilia A mice and hemophilia A mice treated with <i>piggyBac</i> vector expressing full-length FVIII. Scale bar represents 50 µm (x400: original magnification). (C) Total RNA were extracted from the mouse liver treated with <i>piggyBac</i> vectors with 4 weeks interval, and quantified the level of transgene mRNA by qRT-PCR using human FVIII light-chain primers. Expression values were normalized to the level of <i>GAPDH</i> mRNA.</p>", "links"=>[], "tags"=>["vector gene delivery system", "293 T cells", "vector system", "Mouse Model", "Factor VIII", "piggyBac vectors", "Culture media", "300 days", "FVIII cDNA", "Hydrodynamic injection", "iPS cells", "Viral vectors", "blood coagulation time", "safety risks", "piggyBac Transposon Vector", "novel gene transfer strategy", "piggyBac DNA transposon", "Gene therapy", "mice.piggyBac transposon vectors", "hemophilia"], "article_id"=>1141336, "categories"=>["Biological Sciences"], "users"=>["Hideto Matsui", "Naoko Fujimoto", "Noriko Sasakawa", "Yasuhide Ohinata", "Midori Shima", "Shinya Yamanaka", "Mitsuhiko Sugimoto", "Akitsu Hotta"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0104957.g004", "stats"=>{"downloads"=>0, "page_views"=>27, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Phenotypic_correction_of_hemophilia_A_mice_by_injection_of_piggyBac_vectors_/1141336", "title"=>"Phenotypic correction of hemophilia A mice by injection of <i>piggyBac</i> vectors.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-08-15 04:46:29"}
  • {"files"=>["https://ndownloader.figshare.com/files/1638578", "https://ndownloader.figshare.com/files/1638579", "https://ndownloader.figshare.com/files/1638580", "https://ndownloader.figshare.com/files/1638581"], "description"=>"<div><p>Viral vectors have been used for hemophilia A gene therapy. However, due to its large size, full-length Factor VIII (FVIII) cDNA has not been successfully delivered using conventional viral vectors. Moreover, viral vectors may pose safety risks, e.g., adverse immunological reactions or virus-mediated cytotoxicity. Here, we took advantages of the non-viral vector gene delivery system based on <i>piggyBac</i> DNA transposon to transfer the full-length FVIII cDNA, for the purpose of treating hemophilia A. We tested the efficiency of this new vector system in human 293T cells and iPS cells, and confirmed the expression of the full-length FVIII in culture media using activity-sensitive coagulation assays. Hydrodynamic injection of the <i>piggyBac</i> vectors into hemophilia A mice temporally treated with an immunosuppressant resulted in stable production of circulating FVIII for over 300 days without development of anti-FVIII antibodies. Furthermore, tail-clip assay revealed significant improvement of blood coagulation time in the treated mice.<i>piggyBac</i> transposon vectors can facilitate the long-term expression of therapeutic transgenes <i>in vitro</i> and <i>in vivo</i>. This novel gene transfer strategy should provide safe and efficient delivery of FVIII.</p></div>", "links"=>[], "tags"=>["vector gene delivery system", "293 T cells", "vector system", "Mouse Model", "Factor VIII", "piggyBac vectors", "Culture media", "300 days", "FVIII cDNA", "Hydrodynamic injection", "iPS cells", "Viral vectors", "blood coagulation time", "safety risks", "piggyBac Transposon Vector", "novel gene transfer strategy", "piggyBac DNA transposon", "Gene therapy", "mice.piggyBac transposon vectors", "hemophilia"], "article_id"=>1141337, "categories"=>["Biological Sciences"], "users"=>["Hideto Matsui", "Naoko Fujimoto", "Noriko Sasakawa", "Yasuhide Ohinata", "Midori Shima", "Shinya Yamanaka", "Mitsuhiko Sugimoto", "Akitsu Hotta"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0104957.s001", "https://dx.doi.org/10.1371/journal.pone.0104957.s002", "https://dx.doi.org/10.1371/journal.pone.0104957.s003", "https://dx.doi.org/10.1371/journal.pone.0104957.s004"], "stats"=>{"downloads"=>1, "page_views"=>29, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Delivery_of_Full_Length_Factor_VIII_Using_a_piggyBac_Transposon_Vector_to_Correct_a_Mouse_Model_of_Hemophilia_A/1141337", "title"=>"Delivery of Full-Length Factor VIII Using a <i>piggyBac</i> Transposon Vector to Correct a Mouse Model of Hemophilia A", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2014-08-15 04:46:29"}
  • {"files"=>["https://ndownloader.figshare.com/files/1638574"], "description"=>"<p>(A) Schematic diagram of <i>piggyBac</i> vectors expressing EGFP, B-domain–deleted human FVIII, and full-length human FVIII under the control of the human EF1α promoter. The PBaseII vector expresses <i>piggyBac</i> transposase under the control of the CAG promoter. IRES: internal ribosomal entry site. (B) Copy number of genomic <i>piggyBac</i> vectors. Indicated <i>piggyBac</i> vectors were transfected into 293T cells and selected with puromycin resistance. Approximately three months after transduction, genomic DNAs were extracted, and <i>piggyBac</i> vector copy numbers were assessed by real-time PCR using the <i>piggyBac</i> 5′ TR primers. The data are normalized to a haploid genome calculated from the copy number of NANOG gene. *: <i>P</i><0.05 by two-sided Student's <i>t</i> test (n = 3). N.S.: Not significant. (C) The sizes of inserted FVIII cDNA (2,219 bp for BDD and 4,901 bp for full-length FVIII) were confirmed by genomic PCR using the hF8insertC primers flanking the B-domain (indicated as small arrows in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0104957#pone-0104957-g001\" target=\"_blank\">Figure 1A</a>).</p>", "links"=>[], "tags"=>["vector gene delivery system", "293 T cells", "vector system", "Mouse Model", "Factor VIII", "piggyBac vectors", "Culture media", "300 days", "FVIII cDNA", "Hydrodynamic injection", "iPS cells", "Viral vectors", "blood coagulation time", "safety risks", "piggyBac Transposon Vector", "novel gene transfer strategy", "piggyBac DNA transposon", "Gene therapy", "mice.piggyBac transposon vectors", "hemophilia"], "article_id"=>1141333, "categories"=>["Biological Sciences"], "users"=>["Hideto Matsui", "Naoko Fujimoto", "Noriko Sasakawa", "Yasuhide Ohinata", "Midori Shima", "Shinya Yamanaka", "Mitsuhiko Sugimoto", "Akitsu Hotta"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0104957.g001", "stats"=>{"downloads"=>7, "page_views"=>32, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_piggyBac_vectors_to_express_Factor_VIII_cDNAs_/1141333", "title"=>"<i>piggyBac</i> vectors to express Factor VIII cDNAs.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-08-15 04:46:29"}
  • {"files"=>["https://ndownloader.figshare.com/files/1638575"], "description"=>"<p>(A, B) Total mRNAs were extracted from 293T cells (A) or human iPS cells (B), and the level of expression was assessed by quantitative RT-PCR. Expression values were normalized to the level of <i>GAPDH</i> mRNA. (C, D) Secretion of functional FVIII measured by aPTT assay. Culture supernatants of transfected cells were harvested 3 days after medium change and subjected to aPTT assay to measure the coagulation activity of secreted FVIII protein in 293T cells (C) or human iPS cells (D). Recombinant FVIII product was used to generate a standard curve. Normal FVIII activity (100%) represents 1 U/ml ( = 1000 mU/ml). *: <i>P</i><0.05 by two-sided Student's <i>t</i> test (n = 3).</p>", "links"=>[], "tags"=>["vector gene delivery system", "293 T cells", "vector system", "Mouse Model", "Factor VIII", "piggyBac vectors", "Culture media", "300 days", "FVIII cDNA", "Hydrodynamic injection", "iPS cells", "Viral vectors", "blood coagulation time", "safety risks", "piggyBac Transposon Vector", "novel gene transfer strategy", "piggyBac DNA transposon", "Gene therapy", "mice.piggyBac transposon vectors", "hemophilia"], "article_id"=>1141334, "categories"=>["Biological Sciences"], "users"=>["Hideto Matsui", "Naoko Fujimoto", "Noriko Sasakawa", "Yasuhide Ohinata", "Midori Shima", "Shinya Yamanaka", "Mitsuhiko Sugimoto", "Akitsu Hotta"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0104957.g002", "stats"=>{"downloads"=>1, "page_views"=>17, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Full_length_FVIII_can_be_expressed_at_levels_as_high_as_BDD_FVIII_/1141334", "title"=>"Full-length FVIII can be expressed at levels as high as BDD FVIII.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-08-15 04:46:29"}
  • {"files"=>["https://ndownloader.figshare.com/files/1638576"], "description"=>"<p>(A, B) <i>piggyBac</i> vector (25 µg of DNA) expressing either B-domain–deleted (A) or full-length FVIII (B) was introduced into hemophilia A mice (n = 5 each) by hydrodynamic injection without cyclophosphamide treatments. Amount of PBaseII <i>piggyBac</i> transposase (0 µg, 6.25 µg, or 25 µg of DNA) is indicated by symbols. Levels of anti-human FVIII inhibitors in mouse plasma were measured by Bethesda assay. (C, D) <i>piggyBac</i> vector (25 µg of DNA) expressing either B-domain-deleted (C) or full-length FVIII (D) was introduced into hemophilia A mice (n = 7 each) by hydrodynamic injection with cyclophosphamide treatments. Amount of PBaseII <i>piggyBac</i> transposase (0 µg, 6.25 µg or 25 µg of DNA) is indicated by symbols. Levels of FVIII activity in mouse plasma were measured by chromogenic assay. (E, F) Multiple injections boosted the level of FVIII in hemophilia A mice. PB-EF1α-hFVIII(Full)-iP (25 µg) and PBaseII (6.25 µg) vectors were hydrodynamically injected into hemophilia A mice (n = 7 each) three times at intervals of 24 hours or 4 weeks. (E) Level of FVIII activity in mouse plasma was measured by chromogenic assay. (F) Level of anti-human FVIII inhibitor was measured by Bethesda assay.</p>", "links"=>[], "tags"=>["vector gene delivery system", "293 T cells", "vector system", "Mouse Model", "Factor VIII", "piggyBac vectors", "Culture media", "300 days", "FVIII cDNA", "Hydrodynamic injection", "iPS cells", "Viral vectors", "blood coagulation time", "safety risks", "piggyBac Transposon Vector", "novel gene transfer strategy", "piggyBac DNA transposon", "Gene therapy", "mice.piggyBac transposon vectors", "hemophilia"], "article_id"=>1141335, "categories"=>["Biological Sciences"], "users"=>["Hideto Matsui", "Naoko Fujimoto", "Noriko Sasakawa", "Yasuhide Ohinata", "Midori Shima", "Shinya Yamanaka", "Mitsuhiko Sugimoto", "Akitsu Hotta"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0104957.g003", "stats"=>{"downloads"=>4, "page_views"=>30, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Long_term_and_stable_expression_of_FVIII_in_hemophilia_A_mice_/1141335", "title"=>"Long-term and stable expression of FVIII in hemophilia A mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-08-15 04:46:29"}

PMC Usage Stats | Further Information

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Relative Metric

{"start_date"=>"2014-01-01T00:00:00Z", "end_date"=>"2014-12-31T00:00:00Z", "subject_areas"=>[{"subject_area"=>"/Biology and life sciences/Genetics", "average_usage"=>[306, 482]}, {"subject_area"=>"/Biology and life sciences/Microbiology", "average_usage"=>[317]}, {"subject_area"=>"/Medicine and health sciences/Epidemiology", "average_usage"=>[333]}, {"subject_area"=>"/Medicine and health sciences/Hematology", "average_usage"=>[256]}, {"subject_area"=>"/Physical sciences/Physics", "average_usage"=>[266]}]}
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