Brimble, Mark; Morton, Christopher L; Winston, Stephen M; Reeves, Isaiah L; Spence, Yunyu; Cheng, Pei-Hsin; Zhou, Jungfang; ... Davidoff, Andrew M; + view all Brimble, Mark; Morton, Christopher L; Winston, Stephen M; Reeves, Isaiah L; Spence, Yunyu; Cheng, Pei-Hsin; Zhou, Jungfang; Nathwani, Amit C; Thomas, Paul Glwndyr; Souquette, Aisha; Davidoff, Andrew M; - view fewer (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).

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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.

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