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Enhanced liver gene transfer and evasion of preexisting humoral immunity with exosome-enveloped AAV vectors

dc.contributor.authorMELIANI, Amine
dc.contributor.authorBOISGERAULT, Florence
dc.contributor.authorFITZPATRICK, Zachary
dc.contributor.authorMARMIER, Solenne
dc.contributor.authorLEBORGNE, Christian
dc.contributor.authorCOLLAUD, Fanny
dc.contributor.authorSOLA, Marcelo Simon
dc.contributor.authorCHARLES, Severine
dc.contributor.authorRONZITTI, Giuseppe
dc.contributor.authorVIGNAUD, Alban
dc.contributor.authorVAN WITTENBERGHE, Laetitia
dc.contributor.authorMAROLLEAU, Beatrice
dc.contributor.authorJOUEN, Fabienne
hal.structure.identifierChimie et Biologie des Membranes et des Nanoobjets [CBMN]
dc.contributor.authorTAN, Sisareuth
dc.contributor.authorBOYER, Olivier
dc.contributor.authorCHRISTOPHE, Olivier
hal.structure.identifierChimie et Biologie des Membranes et des Nanoobjets [CBMN]
dc.contributor.authorBRISSON, Alain
dc.contributor.authorMAGUIRE, Casey A.
dc.contributor.authorMINGOZZI, Federico
dc.date.accessioned2020-07-09T14:16:42Z
dc.date.available2020-07-09T14:16:42Z
dc.date.issued2017-10-24
dc.identifier.issn2473-9529
dc.identifier.urihttps://oskar-bordeaux.fr/handle/20.500.12278/10287
dc.description.abstractEnResults from clinical trials of liver gene transfer for hemophilia demonstrate the potential of the adeno-associated virus (AAV) vector platform. However, to achieve therapeutic transgene expression, in some cases high vector doses are required, which are associated with a higher risk of triggering anti-capsid cytotoxic T-cell responses. Additionally, anti-AAV preexisting immunity can prevent liver transduction even at low neutralizing antibody (NAb) titers. Here, we describe the use of exosome-associated AAV (exo-AAV) vectors as a robust liver gene delivery system that allows the therapeutic vector dose to be decreased while protecting from preexisting humoral immunity to the capsid. The in vivo efficiency of liver targeting of standard AAV8 or AAV5 and exo-AAV8 or exo-AAV5 vectors expressing human coagulation factor IX (hF. IX) was evaluated. A significant enhancement of transduction efficiency was observed, and in hemophilia B mice treated with 4 x 10(10) vector genomes per kilogram of exo-AAV8 vectors, a staggering; 1 log increase in hF. IX transgene expression was observed, leading to superior correction of clotting time. Enhanced liver expression was also associated with an increase in the frequency of regulatory T cells in lymph nodes. The efficiency of exo- and standard AAV8 vectors in evading preexisting NAbs to the capsid was then evaluated in a passive immunization mouse model and in human sera. Exo-AAV8 gene delivery allowed for efficient transduction even in the presence of moderate NAb titers, thus potentially extending the proportion of subjects eligible for liver gene transfer. Exo-AAV vectors therefore represent a platform to improve the safety and efficacy of liver-directed gene transfer.
dc.title.enEnhanced liver gene transfer and evasion of preexisting humoral immunity with exosome-enveloped AAV vectors
dc.typeArticle de revue
dc.identifier.doi10.1182/bloodadvances.2017010181
dc.subject.halChimie/Matériaux
bordeaux.journalBLOOD ADVANCES
bordeaux.page2019-2031
bordeaux.volume1
bordeaux.hal.laboratoriesInstitut de Chimie & de Biologie des Membranes & des Nano-objets (CBMN) - UMR 5248*
bordeaux.hal.laboratoriesInstitut de Chimie & de Biologie des Membranes & des Nano-objets (CBMN, UMR 5248)
bordeaux.issue23
bordeaux.institutionUniversité de Bordeaux
bordeaux.institutionBordeaux INP
bordeaux.COinSctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.jtitle=BLOOD%20ADVANCES&rft.date=2017-10-24&rft.volume=1&rft.issue=23&rft.spage=2019-2031&rft.epage=2019-2031&rft.eissn=2473-9529&rft.issn=2473-9529&rft.au=MELIANI,%20Amine&BOISGERAULT,%20Florence&FITZPATRICK,%20Zachary&MARMIER,%20Solenne&LEBORGNE,%20Christian&rft.genre=article


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