{"id":"https://openalex.org/W2991994022","doi":"https://doi.org/10.1182/blood.v108.11.763.763","title":"Protease\u2212Activated Receptor 2 (PAR\u22122) as a Novel Target To Prevent Inhibitor Formation to FIX.","display_name":"Protease\u2212Activated Receptor 2 (PAR\u22122) as a Novel Target To Prevent Inhibitor Formation to FIX.","publication_year":2006,"publication_date":"2006-11-16","ids":{"openalex":"https://openalex.org/W2991994022","doi":"https://doi.org/10.1182/blood.v108.11.763.763","mag":"2991994022"},"language":"en","primary_location":{"id":"doi:10.1182/blood.v108.11.763.763","doi":"https://doi.org/10.1182/blood.v108.11.763.763","is_oa":false,"landing_page_url":"https://doi.org/10.1182/blood.v108.11.763.763","pdf_url":null,"source":{"id":"https://openalex.org/S200071133","display_name":"Blood","issn_l":"0006-4971","issn":["0006-4971","1528-0020"],"is_oa":false,"is_in_doaj":false,"is_core":true,"listed_in":["anvur-scientific","cwts-core","dongbi-a","doyens","jufo-3","ki-jl-3","medline","norway-2","poland-200","russia-white-list-1","vabb-shw"],"host_organization":"https://openalex.org/P4310320990","host_organization_name":"Elsevier BV","host_organization_lineage":["https://openalex.org/P4310320990"],"host_organization_lineage_names":["Elsevier BV"],"type":"journal"},"license":null,"license_id":null,"version":"publishedVersion","is_accepted":true,"is_published":true,"raw_source_name":"Blood","raw_type":"journal-article"},"volume":null,"type":"article","indexed_in":["crossref"],"open_access":{"is_oa":false,"oa_status":"closed","oa_url":null,"any_repository_has_fulltext":false},"authorships":[{"author_position":"first","author":{"id":"https://openalex.org/A5070931891","display_name":"Stefano Baila","orcid":null,"observed_orcids":[]},"institutions":[{"id":"https://openalex.org/I1335321130","display_name":"Children's Hospital of Philadelphia","ror":"https://ror.org/01z7r7q48","country_code":"US","type":"funder","lineage":["https://openalex.org/I1335321130"]}],"countries":["US"],"is_corresponding":false,"raw_author_name":"Stefano Baila","raw_affiliation_strings":["Pediatrics, Children\u2019s Hospital of Philadelphia, Philadelphia, PA, USA"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"Pediatrics, Children\u2019s Hospital of Philadelphia, Philadelphia, PA, USA","institution_ids":["https://openalex.org/I1335321130"]}]},{"author_position":"middle","author":{"id":"https://openalex.org/A5061728618","display_name":"Christian Furlan Freguia","orcid":null,"observed_orcids":[]},"institutions":[{"id":"https://openalex.org/I1335321130","display_name":"Children's Hospital of Philadelphia","ror":"https://ror.org/01z7r7q48","country_code":"US","type":"funder","lineage":["https://openalex.org/I1335321130"]}],"countries":["US"],"is_corresponding":false,"raw_author_name":"Christian Furlan Freguia","raw_affiliation_strings":["Pediatrics, Children\u2019s Hospital of Philadelphia, Philadelphia, PA, USA"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"Pediatrics, Children\u2019s Hospital of Philadelphia, Philadelphia, PA, USA","institution_ids":["https://openalex.org/I1335321130"]}]},{"author_position":"middle","author":{"id":"https://openalex.org/A5005544381","display_name":"Nicholas P. Iacobelli","orcid":null,"observed_orcids":[]},"institutions":[{"id":"https://openalex.org/I1335321130","display_name":"Children's Hospital of Philadelphia","ror":"https://ror.org/01z7r7q48","country_code":"US","type":"funder","lineage":["https://openalex.org/I1335321130"]}],"countries":["US"],"is_corresponding":false,"raw_author_name":"Nicholas Iacobelli","raw_affiliation_strings":["Pediatrics, Children\u2019s Hospital of Philadelphia, Philadelphia, PA, USA"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"Pediatrics, Children\u2019s Hospital of Philadelphia, Philadelphia, PA, USA","institution_ids":["https://openalex.org/I1335321130"]}]},{"author_position":"middle","author":{"id":null,"display_name":"Danielle Dunn","orcid":null,"observed_orcids":[]},"institutions":[{"id":"https://openalex.org/I1335321130","display_name":"Children's Hospital of Philadelphia","ror":"https://ror.org/01z7r7q48","country_code":"US","type":"funder","lineage":["https://openalex.org/I1335321130"]}],"countries":["US"],"is_corresponding":false,"raw_author_name":"Danielle Dunn","raw_affiliation_strings":["Pediatrics, Children\u2019s Hospital of Philadelphia, Philadelphia, PA, USA"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"Pediatrics, Children\u2019s Hospital of Philadelphia, Philadelphia, PA, USA","institution_ids":["https://openalex.org/I1335321130"]}]},{"author_position":"middle","author":{"id":"https://openalex.org/A5068778977","display_name":"Joerg Schuettrumpf","orcid":"https://orcid.org/0000-0002-8855-4096","observed_orcids":["https://orcid.org/0000-0002-8855-4096"]},"institutions":[{"id":"https://openalex.org/I1335321130","display_name":"Children's Hospital of Philadelphia","ror":"https://ror.org/01z7r7q48","country_code":"US","type":"funder","lineage":["https://openalex.org/I1335321130"]}],"countries":["US"],"is_corresponding":false,"raw_author_name":"Joerg Schuettrumpf","raw_affiliation_strings":["Pediatrics, Children\u2019s Hospital of Philadelphia, Philadelphia, PA, USA"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"Pediatrics, Children\u2019s Hospital of Philadelphia, Philadelphia, PA, USA","institution_ids":["https://openalex.org/I1335321130"]}]},{"author_position":"middle","author":{"id":"https://openalex.org/A5049298836","display_name":"Federico Mingozzi","orcid":"https://orcid.org/0000-0003-0685-3752","observed_orcids":["https://orcid.org/0000-0003-0685-3752","https://orcid.org/0000-0002-6607-0058","https://orcid.org/0009-0002-9658-6466"]},"institutions":[{"id":"https://openalex.org/I1335321130","display_name":"Children's Hospital of Philadelphia","ror":"https://ror.org/01z7r7q48","country_code":"US","type":"funder","lineage":["https://openalex.org/I1335321130"]}],"countries":["US"],"is_corresponding":false,"raw_author_name":"Federico Mingozzi","raw_affiliation_strings":["Pediatrics, Children\u2019s Hospital of Philadelphia, Philadelphia, PA, USA"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"Pediatrics, Children\u2019s Hospital of Philadelphia, Philadelphia, PA, USA","institution_ids":["https://openalex.org/I1335321130"]}]},{"author_position":"middle","author":{"id":"https://openalex.org/A5038622138","display_name":"Patricia Andrade\u2010Gordon","orcid":null,"observed_orcids":[]},"institutions":[],"countries":[],"is_corresponding":false,"raw_author_name":"Patricia Andrade-Gordon","raw_affiliation_strings":["Research and Development, Johnson & Johnson Pharmaceutical, Spring House, PA, USA"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"Research and Development, Johnson & Johnson Pharmaceutical, Spring House, PA, USA","institution_ids":[]}]},{"author_position":"last","author":{"id":"https://openalex.org/A5083658192","display_name":"Valder R. Arruda","orcid":"https://orcid.org/0000-0002-8100-5481","observed_orcids":["https://orcid.org/0000-0002-8100-5481"]},"institutions":[{"id":"https://openalex.org/I1335321130","display_name":"Children's Hospital of Philadelphia","ror":"https://ror.org/01z7r7q48","country_code":"US","type":"funder","lineage":["https://openalex.org/I1335321130"]},{"id":"https://openalex.org/I79576946","display_name":"University of Pennsylvania","ror":"https://ror.org/00b30xv10","country_code":"US","type":"education","lineage":["https://openalex.org/I79576946"]}],"countries":["US"],"is_corresponding":false,"raw_author_name":"Valder R. Arruda","raw_affiliation_strings":["Pediatrics, Children\u2019s Hospital of Philadelphia, Philadelphia, PA, USA","Pediatrics, University of Pennsylvania, Philadelphia, PA, USA"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"Pediatrics, Children\u2019s Hospital of Philadelphia, Philadelphia, PA, USA","institution_ids":["https://openalex.org/I1335321130"]},{"raw_affiliation_string":"Pediatrics, University of Pennsylvania, Philadelphia, PA, USA","institution_ids":["https://openalex.org/I79576946"]}]}],"institutions":[],"countries_distinct_count":1,"institutions_distinct_count":2,"corresponding_author_ids":[],"corresponding_institution_ids":[],"apc_list":{"value":5500,"currency":"USD","value_usd":5500},"apc_paid":null,"fwci":0.0,"has_fulltext":false,"cited_by_count":0,"citation_normalized_percentile":{"value":0.36652627,"is_in_top_1_percent":false,"is_in_top_10_percent":false},"cited_by_percentile_year":null,"biblio":{"volume":"108","issue":"11","first_page":"763","last_page":"763"},"is_retracted":false,"is_paratext":false,"is_xpac":false,"primary_topic":{"id":"https://openalex.org/T10613","display_name":"Virus-based gene therapy research","score":0.5268999934196472,"subfield":{"id":"https://openalex.org/subfields/1311","display_name":"Genetics"},"field":{"id":"https://openalex.org/fields/13","display_name":"Biochemistry, Genetics and Molecular Biology"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}},"topics":[{"id":"https://openalex.org/T10613","display_name":"Virus-based gene therapy research","score":0.5268999934196472,"subfield":{"id":"https://openalex.org/subfields/1311","display_name":"Genetics"},"field":{"id":"https://openalex.org/fields/13","display_name":"Biochemistry, Genetics and Molecular Biology"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}},{"id":"https://openalex.org/T11280","display_name":"Hemophilia Treatment and Research","score":0.4287000000476837,"subfield":{"id":"https://openalex.org/subfields/2720","display_name":"Hematology"},"field":{"id":"https://openalex.org/fields/27","display_name":"Medicine"},"domain":{"id":"https://openalex.org/domains/4","display_name":"Health Sciences"}},{"id":"https://openalex.org/T10725","display_name":"RNA Interference and Gene Delivery","score":0.005799999926239252,"subfield":{"id":"https://openalex.org/subfields/1312","display_name":"Molecular Biology"},"field":{"id":"https://openalex.org/fields/13","display_name":"Biochemistry, Genetics and Molecular Biology"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}}],"keywords":[{"id":"https://openalex.org/keywords/protease-activated-receptor-2","display_name":"protease-activated receptor 2","score":0.9980000257492065},{"id":"https://openalex.org/keywords/factor-ix","display_name":"factor IX","score":0.5540000200271606},{"id":"https://openalex.org/keywords/hemophilia-b","display_name":"hemophilia B","score":0.9160000085830688},{"id":"https://openalex.org/keywords/aav-serotype-2","display_name":"AAV serotype 2","score":0.7210000157356262},{"id":"https://openalex.org/keywords/aav1","display_name":"AAV1","score":0.39800000190734863},{"id":"https://openalex.org/keywords/inhibitor-formation","display_name":"inhibitor formation","score":0.6299999952316284},{"id":"https://openalex.org/keywords/protease-activated-receptor-1","display_name":"protease-activated receptor 1","score":0.7009999752044678},{"id":"https://openalex.org/keywords/transgene-stability","display_name":"transgene stability","score":0.40299999713897705},{"id":"https://openalex.org/keywords/factor-ix-replacement-therapy","display_name":"factor IX replacement therapy","score":0.33799999952316284},{"id":"https://openalex.org/keywords/bethesda-assay","display_name":"Bethesda assay","score":0.7210000157356262}],"concepts":[{"id":"https://openalex.org/C102230213","wikidata":"https://www.wikidata.org/wiki/Q430117","display_name":"Transgene","level":3,"score":0.6228794455528259},{"id":"https://openalex.org/C8891405","wikidata":"https://www.wikidata.org/wiki/Q1059","display_name":"Immune system","level":2,"score":0.5969595909118652},{"id":"https://openalex.org/C159654299","wikidata":"https://www.wikidata.org/wiki/Q79460","display_name":"Antibody","level":2,"score":0.5756560564041138},{"id":"https://openalex.org/C111599444","wikidata":"https://www.wikidata.org/wiki/Q213901","display_name":"Genetic enhancement","level":3,"score":0.568500280380249},{"id":"https://openalex.org/C203014093","wikidata":"https://www.wikidata.org/wiki/Q101929","display_name":"Immunology","level":1,"score":0.47362229228019714},{"id":"https://openalex.org/C2781221834","wikidata":"https://www.wikidata.org/wiki/Q425360","display_name":"Factor IX","level":2,"score":0.4567088484764099},{"id":"https://openalex.org/C86803240","wikidata":"https://www.wikidata.org/wiki/Q420","display_name":"Biology","level":0,"score":0.45076239109039307},{"id":"https://openalex.org/C182220744","wikidata":"https://www.wikidata.org/wiki/Q7251226","display_name":"Proteases","level":3,"score":0.4284564256668091},{"id":"https://openalex.org/C71924100","wikidata":"https://www.wikidata.org/wiki/Q11190","display_name":"Medicine","level":0,"score":0.3631118834018707},{"id":"https://openalex.org/C98274493","wikidata":"https://www.wikidata.org/wiki/Q128406","display_name":"Pharmacology","level":1,"score":0.3269491195678711},{"id":"https://openalex.org/C126322002","wikidata":"https://www.wikidata.org/wiki/Q11180","display_name":"Internal medicine","level":1,"score":0.22335919737815857},{"id":"https://openalex.org/C104317684","wikidata":"https://www.wikidata.org/wiki/Q7187","display_name":"Gene","level":2,"score":0.15291303396224976},{"id":"https://openalex.org/C181199279","wikidata":"https://www.wikidata.org/wiki/Q8047","display_name":"Enzyme","level":2,"score":0.07826179265975952},{"id":"https://openalex.org/C55493867","wikidata":"https://www.wikidata.org/wiki/Q7094","display_name":"Biochemistry","level":1,"score":0.0}],"mesh":[],"locations_count":1,"locations":[{"id":"doi:10.1182/blood.v108.11.763.763","doi":"https://doi.org/10.1182/blood.v108.11.763.763","is_oa":false,"landing_page_url":"https://doi.org/10.1182/blood.v108.11.763.763","pdf_url":null,"source":{"id":"https://openalex.org/S200071133","display_name":"Blood","issn_l":"0006-4971","issn":["0006-4971","1528-0020"],"is_oa":false,"is_in_doaj":false,"is_core":true,"listed_in":["anvur-scientific","cwts-core","dongbi-a","doyens","jufo-3","ki-jl-3","medline","norway-2","poland-200","russia-white-list-1","vabb-shw"],"host_organization":"https://openalex.org/P4310320990","host_organization_name":"Elsevier BV","host_organization_lineage":["https://openalex.org/P4310320990"],"host_organization_lineage_names":["Elsevier BV"],"type":"journal"},"license":null,"license_id":null,"version":"publishedVersion","is_accepted":true,"is_published":true,"raw_source_name":"Blood","raw_type":"journal-article"}],"best_oa_location":null,"sustainable_development_goals":[{"score":0.9940000176429749,"id":"https://metadata.un.org/sdg/3","display_name":"Good health and well-being"}],"sustainable_development_goals_aurora":[{"score":0.6200000047683716,"id":"https://metadata.un.org/sdg/3","display_name":"Good health and well-being"}],"study_designs":[],"awards":[],"funders":[],"has_content":{"grobid_xml":false,"pdf":false},"content_urls":null,"referenced_works_count":0,"referenced_works":[],"related_works":["https://openalex.org/W2034991432","https://openalex.org/W1527151999","https://openalex.org/W2582436979","https://openalex.org/W1983301471","https://openalex.org/W2034598016","https://openalex.org/W1807214165","https://openalex.org/W4232383651","https://openalex.org/W2565904163","https://openalex.org/W2065451039","https://openalex.org/W1971168066"],"abstract_inverted_index":{"Abstract":[0],"Direct":[1],"intramuscular":[2],"injection":[3,30,174,397,430],"(IM)":[4],"of":[5,51,93,115,125,137,175,188,198,274,290,293,317,363,411,431,440,449,457,492],"adeno\u2212associated":[6],"viral":[7],"(AAV)":[8],"serotype":[9],"2":[10],"in":[11,64,68,74,107,252,262,271,304,314,321,338,342,377,403,483,502,506],"humans":[12],"with":[13,392,455],"hemophilia":[14,507],"B":[15],"(HB)":[16],"is":[17,55,97],"a":[18,65,90,143,258,335,426,458,481,499],"promising":[19],"therapeutic":[20,39],"strategy":[21,58,144],"since":[22,59],"muscle":[23],"biopsies":[24],"obtained":[25],">3":[26],"years":[27],"after":[28],"vector":[29,238,260,306,396],"demonstrated":[31,88],"stable":[32,194],"local":[33],"gene":[34,154,508],"expression.":[35],"However":[36],"to":[37,72,81,133,145,149,156,220,242,249,308,319,349,357,399,423,466,487],"achieve":[38],"FIX":[40,151,186,207,221,224,250,272,281,320,393,400,432,450,467,488],"levels":[41,70,187,273],"using":[42,443],"AAV\u22122":[43,73],"would":[44],"required":[45],"hundreds":[46],"IM":[47,173],"injections.":[48],"The":[49],"use":[50],"alternate":[52],"AAV":[53],"serotypes":[54],"an":[56,104],"attractive":[57],"AAV\u22121":[60],"or":[61,120,127,244,373],"AAV\u22126,":[62],"resulted":[63,270,313],">10\u2212fold":[66],"increase":[67,303],"transgene":[69,83],"compared":[71],"large":[75],"animals,":[76],"but":[77],"the":[78,82,150,196,199,285,305,315,339,343,421,447,484],"immune":[79,111,147,485],"response":[80,486],"product":[84],"has":[85],"been":[86],"consistently":[87],"as":[89,142,227],"major":[91],"limitation":[92],"this":[94],"strategy.":[95],"There":[96],"growing":[98],"evidence":[99],"that":[100,478,490],"blood":[101],"proteases":[102],"play":[103,480],"important":[105],"role":[106,482],"modulating":[108],"inflammatory":[109],"and":[110,162,169,203,276,328,366,385,409,489,510],"responses":[112,148],"through":[113],"activation":[114,439],"PARs.":[116],"Mice":[117],"lacking":[118],"PAR\u22121(\u2212/\u2212)":[119,243],"PAR\u22122(\u2212/\u2212)":[121,268],"alleles":[122],"presented":[123],"amelioration":[124],"immune\u2212":[126],"infection\u2212mediated":[128],"diseases.":[129],"Here":[130],"we":[131],"sought":[132,348],"determine":[134],"whether":[135],"inhibition":[136,417,491],"PARs":[138,479],"could":[139,497],"be":[140,498],"used":[141,160],"prevent":[146],"following":[152,395],"AAV\u2212mediated":[153],"transfer":[155],"skeletal":[157],"muscle.":[158],"We":[159,255,347],"PAR\u22121":[161],"PAR\u22122":[163,180,214,263,294,323,344,364,367,383,406,413,416,441,493],"knockout":[164],"mice":[165,171,182,216,292,369,436],"on":[166],"C57Bl/6":[167],"background":[168],"littermate":[170],"received":[172],"AAV1\u2212CMV\u2212hFIX.":[176],"At":[177,265,284],"dose":[178,261,266,307],"5x1011vg/kg,":[179],"(\u2212/\u2212)":[181,324,345,365,384],"(n=5)":[183],"exhibited":[184],"circulating":[185],"500\u00b1":[189],"99ng/ml":[190],"(8\u201310%)":[191],"which":[192,222],"remained":[193],"for":[195,206,280,351,512],"duration":[197],"experiment":[200],"(10":[201],"weeks),":[202],"no":[204,278],"antibodies":[205,219,248,279,298],"were":[208,240,282,453],"detected":[209,402],"(n=5).":[210],"In":[211,425],"contrast,":[212],"all":[213,253],"(+/+)":[215,368,407],"(n=4)":[217],"developed":[218,251,296],"inhibits":[223],"clotting":[225],"activity,":[226],"determined":[228],"by":[229,354,442],"Bethesda":[230],"assay":[231,350,356],"(2.1\u00b1":[232],"0.6":[233],"BU).":[234,301],"However,":[235],"when":[236],"similar":[237],"doses":[239],"delivered":[241],"PAR\u22121(+/+)":[245],"(n=4/genotype)":[246],"mice,":[247,326,331],"animals.":[254],"next":[256],"tested":[257],"higher":[259],"models.":[264],"1x1012vg/kg,":[267],"mice(n=7)":[269],"1,500\u00b1353ng/ml,":[275],"again":[277],"detected.":[283],"same":[286],"dose,":[287],"6":[288],"out":[289],"10":[291],"(+/+)/(+/\u2212)":[295],"inhibitory":[297],"(1.8\u00b1":[299],"0.7":[300],"Further":[302],"5":[309,412],"x":[310],"1012":[311],"vg/kg":[312],"development":[316],"inhibitor":[318,504],"both":[322],"(4/11":[325],"36%)":[327],"PAR\u22122(+/+)/(+/\u2212)":[329],"(10/17":[330],"60%).":[332],"This":[333],"suggests":[334],"threshold":[336],"value":[337],"protective":[340],"effect":[341],"model.":[346],"FIX\u2212specific":[352],"T\u2212cell":[353],"ELISPOT":[355],"quantify":[358],"IFN\u2212\u03b3":[359,378],"secretion":[360,379],"from":[361],"splenocytes":[362],"injected":[370],"at":[371],"5x1011":[372],"1x1012vg/kg.":[374],"No":[375],"difference":[376],"was":[380,401],"observed":[381],"between":[382],"their":[386],"controls.":[387],"Moreover,":[388],"upon":[389,437],"repeated":[390],"challenges":[391],"protein":[394,433],"antibody":[398,451,464],"only":[404],"1/4":[405],"mouse":[408],"none":[410],"(\u2212/\u2212).":[414],"Thus,":[415,462],"does":[418],"not":[419,495],"compromise":[420],"tolerance":[422],"FIX.":[424],"different":[427],"model,":[428],"intravenous":[429],"into":[434],"normal":[435],"simultaneous":[438],"specific":[444],"agonist":[445],"peptide":[446,460],"rates":[448],"formation":[452,465,505],"comparable":[454],"those":[456],"control":[459],"group.":[461],"PAR\u22122\u2212mediating":[463],"may":[468],"differ":[469],"among":[470],"distinct":[471],"immunologic":[472],"challenges.":[473],"Together,":[474],"these":[475],"data":[476],"suggest":[477],"(but":[494],"PAR\u22121)":[496],"novel":[500],"target":[501],"preventing":[503],"therapy":[509],"potentially":[511],"protein\u2212based":[513],"therapy.":[514]},"counts_by_year":[],"updated_date":"2026-10-09T09:14:12.587421","created_date":"2019-12-13T00:00:00"}
