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JCI Insight. 2018 Jun 21;3(12). pii: 120474. doi: 10.1172/jci.insight.120474. eCollection 2018 Jun 21.

Double-stranded RNA innate immune response activation from long-term adeno-associated virus vector transduction.

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Gene Therapy Center.
Division of Pharmacoengineering and Molecular Pharmaceutics, School of Pharmacy.
Lineberger Comprehensive Cancer Center.
Depatment of Ophthalmology.
Department of Pharmacology.
Department of Pediatrics, School of Medicine, and.
Carolina Institute for Developmental Disabilities, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.


Data from clinical trials for hemophilia B using adeno-associated virus (AAV) vectors have demonstrated decreased transgenic coagulation factor IX (hFIX) expression 6-10 weeks after administration of a high vector dose. While it is likely that capsid-specific cytotoxic T lymphocytes eliminate vector-transduced hepatocytes, thereby resulting in decreased hFIX, this observation is not intuitively consistent with restored hFIX levels following prednisone application. Although the innate immune response is immediately activated following AAV vector infection via TLR pathways, no studies exist regarding the role of the innate immune response at later time points after AAV vector transduction. Herein, activation of the innate immune response in cell lines, primary human hepatocytes, and hepatocytes in a human chimeric mouse model was observed at later time points following AAV vector transduction. Mechanistic analysis demonstrated that the double-stranded RNA (dsRNA) sensor MDA5 was necessary for innate immune response activation and that transient knockdown of MDA5, or MAVS, decreased IFN-β expression while increasing transgene production in AAV-transduced cells. These results both highlight the role of the dsRNA-triggered innate immune response in therapeutic transgene expression at later time points following AAV transduction and facilitate the execution of effective strategies to block the dsRNA innate immune response in future clinical trials.


Gene therapy; Immunology; Innate immunity; Therapeutics

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