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

Shao, Wenwei; Earley, Lauriel F.; Chai, Zhixin; Chen, Xiaojing; Sun, Junjiang; He, Ting; Deng, Meng; Hirsch, Matthew; Ting, Jenny P.Y.; Samulski, R. Jude; Li, Chengwen

doi:10.1172/jci.insight.120474

Cited by 79 publications

(88 citation statements)

References 49 publications

(68 reference 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%

“…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%

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Human Immune Responses to Adeno-Associated Virus (AAV) Vectors

2020

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Recombinant adeno-associated virus (rAAV) vectors are one of the most promising in vivo gene delivery tools. Several features make rAAV vectors an ideal platform for gene transfer. However, the high homology with the parental wild-type virus, which often infects humans, poses limitations in terms of immune responses associated with this vector platform. Both humoral and cell-mediated immunity to wild-type AAV have been documented in healthy donors, and, at least in the case of anti-AAV antibodies, have been shown to have a potentially high impact on the outcome of gene transfer. While several factors can contribute to the overall immunogenicity of rAAV vectors, vector design and the total vector dose appear to be responsible of immune-mediated toxicities. While preclinical models have been less than ideal in predicting the outcome of gene transfer in humans, the current preclinical body of evidence clearly demonstrates that rAAV vectors can trigger both innate and adaptive immune responses. Data gathered from clinical trials offers key learnings on the immunogenicity of AAV vectors, highlighting challenges as well as the potential strategies that could help unlock the full therapeutic potential of in vivo gene transfer.

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Section: Post-treatment Immune Responses Against Aav Vectors Innate Imentioning

confidence: 99%

Section: Post-treatment Immune Responses Against Aav Vectors Innate Imentioning

confidence: 99%

Human Immune Responses to Adeno-Associated Virus (AAV) Vectors

2020

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“…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%

Subgenomic satellite particle generation in recombinant AAV vectors results from DNA lesion/breakage and non-homologous end joining

Zhang

Guo

et al. 2020

Preprint

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Recombinant AAV (rAAV) vectors have been developed for therapeutic treatment of genetic diseases. Nevertheless, current rAAV vectors administered to patients often contain non-vector related DNA contaminants. Here, we present a thorough molecular analysis of the configuration of non-standard AAV genomes generated during rAAV production. In addition to the sub-vector genomic size particles containing incomplete AAV genomes, our results found that rAAV preparations were contaminated with multiple categories of subgenomic particles with either snapback genomes or vector genomes with deletions in the mid regions. Through CRISPR and restriction enzyme-based in vivo and in vitro modeling, we identified that the main mechanism leading to the formation of non-canonical genome particles occurred through nonhomologous end joining of fragmented vector genomes caused by genome lesions or DNA breaks that were generated by the host cell/environment. The results of this study advance our understanding of AAV vectors and provide new clues on improving vector efficiency and safety profile for use in human gene therapy.

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“…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%

Translating CRISPR-Cas Therapeutics: Approaches and Challenges

et al. 2020

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CRISPR-Cas clinical trials have begun, offering a first glimpse at how DNA and RNA targeting could enable therapies for many genetic and epigenetic human diseases. The speedy progress of CRISPR-Cas from discovery and adoption to clinical use is built on decades of traditional gene therapy research and belies the multiple challenges that could derail the successful translation of these new modalities. Here, we review how CRISPR-Cas therapeutics are translated from technological systems to therapeutic modalities, paying particular attention to the therapeutic cascade from cargo to delivery vector, manufacturing, administration, pipelines, safety, and therapeutic target profiles. We also explore potential solutions to some of the obstacles facing successful CRISPR-Cas translation. We hope to illuminate how CRISPR-Cas is brought from the academic bench toward use in the clinic.

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

Cited by 79 publications

References 49 publications

Human Immune Responses to Adeno-Associated Virus (AAV) Vectors

Human Immune Responses to Adeno-Associated Virus (AAV) Vectors

Subgenomic satellite particle generation in recombinant AAV vectors results from DNA lesion/breakage and non-homologous end joining

Translating CRISPR-Cas Therapeutics: Approaches and Challenges

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