2018
DOI: 10.1172/jci.insight.120474
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Double-stranded RNA innate immune response activation from long-term adeno-associated virus vector transduction

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Cited by 79 publications
(88 citation statements)
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“…An intriguing hypothesis is that, in addition to the vector DNA genome, double-stranded RNA (dsRNA) may participate to the induction of innate immunity to rAAV (73). According to this study, dsRNAs are produced by the promoter activity of the ITRs.…”
Section: Post-treatment Immune Responses Against Aav Vectors Innate Imentioning
confidence: 99%
See 1 more Smart Citation
“…An intriguing hypothesis is that, in addition to the vector DNA genome, double-stranded RNA (dsRNA) may participate to the induction of innate immunity to rAAV (73). According to this study, dsRNAs are produced by the promoter activity of the ITRs.…”
Section: Post-treatment Immune Responses Against Aav Vectors Innate Imentioning
confidence: 99%
“…Accumulation of dsRNAs would, in turn, stimulates the MDA5 sensor in human hepatocytes transduced with AAV, leading to the expression of type I IFNs. Interestingly, the blockade of MDA5 decreased the IFN response and improved transgene expression in transduced cells in vitro (73). Although this hypothesis is not yet supported by clinical data, it may explain why cellular responses are sometimes initiated weeks after vector administration in clinical trials, a timeframe that is consistent with the dsRNA synthesis in vivo (51,74).…”
Section: Post-treatment Immune Responses Against Aav Vectors Innate Imentioning
confidence: 99%
“…As suggested in Figure 7, subgenome particles with a promoter can produce dsRNA which will be detrimental to long term gene expression. Although dsRNA was investigated in AAV vectors (10,11), here we identified SBG as the true source for such dsRNA formation. In addition, the SBG containing only the promoter can potentially cause tumorigenesis events in the host cells or in human patients (12).…”
Section: Discussionmentioning
confidence: 91%
“…57 Multiple studies have elucidated some of the mechanisms of innate immune activation by AAVs, including binding by TLR9 of unmethylated CpG dinucleotides in the AAV genome, leading to activation of the MyD88/NF-jB pathway, [58][59][60] and recognition by MDA5 of long dsRNAs created by bidirectional transcription from the AAV episome. 61 These pro-inflammatory signals result in substantial transcriptional changes, inducing an antiviral state within the target cell, and expression of immune-stimulating cytokines that allow for a robust adaptive immune response. 62 In the clinic, patients' cytokine levels are routinely monitored, and sometimes they are modulated with corticosteroids.…”
Section: Crispr-cas Therapeutics Development 257mentioning
confidence: 99%