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Pre-existing immunity to a nucleic acid contaminant-derived antigen mediates transaminitis and resultant diminished transgene expression in a mouse model of hepatic rAAV-mediated gene transfer

Brimble, Mark; Morton, Christopher L; Winston, Stephen M; Reeves, Isaiah L; Spence, Yunyu; Cheng, Pei-Hsin; Zhou, Jungfang; ... Davidoff, Andrew M; + view all (2024) Pre-existing immunity to a nucleic acid contaminant-derived antigen mediates transaminitis and resultant diminished transgene expression in a mouse model of hepatic rAAV-mediated gene transfer. Human Gene Therapy 10.1089/hum.2023.188. (In press). Green open access

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Abstract

Liver injury with concomitant loss of therapeutic transgene expression can be a clinical sequela of systemic administration of rAAV when used for gene therapy, and a significant barrier to treatment efficacy. Despite this, it has been difficult to replicate this phenotype in preclinical models, thereby limiting the field’s ability to systematically investigate underlying biological mechanisms and develop interventions. Prior animal models have focused on capsid and transgene-related immunogenicity but the impact of concurrently present non-transgene or vector antigens on therapeutic efficacy, such as those derived from contaminating nucleic acids within rAAV preps, has yet to be investigated. Here, using Ad5-CMV_GFP immunized immunocompetent BALB/cJ mice, and a coagulation factor VIII expressing rAAV preparation that contains GFP cDNA packaged as P5-associated contaminants, we establish a model to induce transaminitis and observe concomitant therapeutic efficacy reduction after rAAV administration. We observed strong epitope-specific anti-GFP responses in splenic CD8+ T-cells when GFP cDNA was delivered as a P5-associated contaminant of rAAV, which coincided and correlated with alanine and aspartate aminotransferase elevations. Further, we report a significant reduction in detectable circulating FVIII protein, as compared to control mice. Lastly, we observed an elevation in the detection of AAV8 capsid-specific T-cells when GFP was delivered either as a contaminant or transgene to Ad5-CMV_GFP immunized mice. We present this model as a potential tool to study the underlying biology of post-AAV hepatotoxicity and demonstrate the potential for T-cell responses against proteins produced from AAV encapsidated non-therapeutic nucleic acids, to interfere with efficacious gene transfer.

Type: Article
Title: Pre-existing immunity to a nucleic acid contaminant-derived antigen mediates transaminitis and resultant diminished transgene expression in a mouse model of hepatic rAAV-mediated gene transfer
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1089/hum.2023.188
Publisher version: https://doi.org/10.1089/hum.2023.188
Language: English
Additional information: © The Author(s), 2024. This is an Open Access article distributed under the terms of the Creative Commons Attribution Licence (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. https://creativecommons.org/licenses/by/4.0/
Keywords: Adenovirus, Vector
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Haematology
URI: https://discovery.ucl.ac.uk/id/eprint/10188325
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