Interindividual variability in transgene mRNA and protein production following adeno-associated virus gene therapy for hemophilia A

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dc.contributor.authorFong, Sylvia
dc.contributor.authorYates, Bridget
dc.contributor.authorSihn, Choong-Ryoul
dc.contributor.authorMattis, Aras N
dc.contributor.authorMitchell, Nina
dc.contributor.authorLiu, Su
dc.contributor.authorRussell, Chris B
dc.contributor.authorKim, Benjamin
dc.contributor.authorLawal, Adebayo
dc.contributor.authorRangarajan, Savita
dc.contributor.authorLester, Will
dc.contributor.authorBunting, Stuart
dc.contributor.authorPierce, Glenn F
dc.contributor.authorPasi, K John
dc.contributor.authorWong, Wing Yen
dc.contributor.departmentHaematologyen_US
dc.contributor.roleMedical and Dentalen_US
dc.contributor.trustauthorLester, Will
dc.date.accessioned2024-06-17T10:02:09Z
dc.date.available2024-06-17T10:02:09Z
dc.date.issued2022-04-11
dc.description.abstractFactor VIII gene transfer with a single intravenous infusion of valoctocogene roxaparvovec (AAV5-hFVIII-SQ) has demonstrated clinical benefits lasting 5 years to date in people with severe hemophilia A. Molecular mechanisms underlying sustained AAV5-hFVIII-SQ-derived FVIII expression have not been studied in humans. In a substudy of the phase 1/2 clinical trial ( NCT02576795 ), liver biopsy samples were collected 2.6-4.1 years after gene transfer from five participants. Primary objectives were to examine effects on liver histopathology, determine the transduction pattern and percentage of hepatocytes transduced with AAV5-hFVIII-SQ genomes, characterize and quantify episomal forms of vector DNA and quantify transgene expression (hFVIII-SQ RNA and hFVIII-SQ protein). Histopathology revealed no dysplasia, architectural distortion, fibrosis or chronic inflammation, and no endoplasmic reticulum stress was detected in hepatocytes expressing hFVIII-SQ protein. Hepatocytes stained positive for vector genomes, showing a trend for more cells transduced with higher doses. Molecular analysis demonstrated the presence of full-length, inverted terminal repeat-fused, circular episomal genomes, which are associated with long-term expression. Interindividual differences in transgene expression were noted despite similar successful transduction, possibly influenced by host-mediated post-transduction mechanisms of vector transcription, hFVIII-SQ protein translation and secretion. Overall, these results demonstrate persistent episomal vector structures following AAV5-hFVIII-SQ administration and begin to elucidate potential mechanisms mediating interindividual variability.en_US
dc.identifier.citationFong S, Yates B, Sihn CR, Mattis AN, Mitchell N, Liu S, Russell CB, Kim B, Lawal A, Rangarajan S, Lester W, Bunting S, Pierce GF, Pasi KJ, Wong WY. Interindividual variability in transgene mRNA and protein production following adeno-associated virus gene therapy for hemophilia A. Nat Med. 2022 Apr;28(4):789-797. doi: 10.1038/s41591-022-01751-0. Epub 2022 Apr 11en_US
dc.identifier.doi10.1038/s41591-022-01751-0
dc.identifier.eissn1546-170X
dc.identifier.issn1078-8956
dc.identifier.pmid35411075
dc.identifier.urihttp://hdl.handle.net/20.500.14200/4881
dc.language.isoenen_US
dc.publisherNature Publishing Companyen_US
dc.relation.urlhttp://www.nature.com/nm/index.htmlen_US
dc.rights© 2022. The Author(s).
dc.source.journaltitleNature Medicineen_US
dc.subjectPharmacologyen_US
dc.subjectClinical pathologyen_US
dc.titleInterindividual variability in transgene mRNA and protein production following adeno-associated virus gene therapy for hemophilia Aen_US
dc.typeArticleen_US
dc.typeOtheren_US
dspace.entity.typePublication
oa.grant.openaccessnaen_US
rioxxterms.versionNAen_US
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