Activation of Innate Immunity by Therapeutic Nucleic Acids

Bishani, Ali; Chernolovskaya, E. L.

doi:10.3390/ijms222413360

Cited by 24 publications

(17 citation statements)

References 155 publications

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“…They are not associated with Watson-Crick base pairing. For example, phosphorothioate oligonucleotides (PS) are known to interact with a broad range of proteins causing cytotoxicity 10 or the immune system activation commonly observed for all OGT agents 11 , 12 . ASO agents and Dz were found to activate proinflammatory response due to both non-natural chemical modifications and the presence of unmethylated CpG sequences.…”

Section: Introductionmentioning

confidence: 99%

Specificity of oligonucleotide gene therapy (OGT) agents

Nedorezova¹,

Dubovichenko²,

Belyaeva³

et al. 2022

Theranostics

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Oligonucleotide gene therapy (OGT) agents (e. g. antisense, deoxyribozymes, siRNA and CRISPR/Cas) are promising therapeutic tools. Despite extensive efforts, only few OGT drugs have been approved for clinical use. Besides the problem of efficient delivery to targeted cells, hybridization specificity is a potential limitation of OGT agents. To ensure tight binding, a typical OGT agent hybridizes to the stretch of 15-25 nucleotides of a unique targeted sequence. However, hybrids of such lengths tolerate one or more mismatches under physiological conditions, the problem known as the affinity/specificity dilemma. Here, we assess the scale of this problem by analyzing OGT hybridization-dependent off-target effects (HD OTE) in vitro , in animal models and clinical studies. All OGT agents except deoxyribozymes exhibit HD OTE in vitro , with most thorough evidence of poor specificity reported for siRNA and CRISPR/Cas9. Notably, siRNA suppress non-targeted genes due to (1) the partial complementarity to mRNA 3'-untranslated regions (3'-UTR), and (2) the antisense activity of the sense strand. CRISPR/Cas9 system can cause hundreds of non-intended dsDNA breaks due to low specificity of the guide RNA, which can limit therapeutic applications of CRISPR/Cas9 by ex-vivo formats. Contribution of this effects to the observed in vivo toxicity of OGT agents is unclear and requires further investigation. Locked or peptide nucleic acids improve OGT nuclease resistance but not specificity. Approaches that use RNA marker dependent (conditional) activation of OGT agents may improve specificity but require additional validation in cell culture and in vivo .

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Section: Introductionmentioning

confidence: 99%

Specificity of oligonucleotide gene therapy (OGT) agents

Nedorezova¹,

Dubovichenko²,

Belyaeva³

et al. 2022

Theranostics

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show abstract

“…[40][41] In support of TLR receptor involvement, siRNA-mediated knockdown of TLR3 and/or TLR7 resulted in a ~70% reduction in TNF expression following G-rich L-RNA treatment as compared to WT cells (Figure S8). While TLR engagement and immune systemrelated cytotoxicity has been documented for synthetic oligonucleotides [42][43][44][45] , including those with unnatural sugars 46 , strong immunostimulatory actives by G-rich L-RNA was surprising given the complete stereochemical inversion of the sugar backbone, as well as prior reports concluding that L-oligonucleotides have very low immunogenic potential. 9,47 These prior studies, however, did not examine G-rich L-RNAs, highlighting the importance of sequence activity relationship studies.…”

Section: Immunitymentioning

confidence: 99%

The influence of chirality on the behavior of oligonucleotides inside cells: revealing the potent cytotoxicity of G-rich l-RNA

Sczepanski

2023

Chem. Sci.

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“…Upon ligand binding, PRRs activate downstream signaling pathways via corresponding signaling molecules and finally induce the production of inflammatory cytokines and type I IFNs through the transcription factors, nuclear factor (NF)-κB and interferon regulatory factors (IRFs) ( Bishani and Chernolovskaya, 2021 ). Furthermore, they activate the mitogen-activated protein kinase signaling cascade ( Chen, 2005 ).…”

Section: Na Sensing By Prrsmentioning

confidence: 99%

Pathophysiological Role of Nucleic Acid-Sensing Pattern Recognition Receptors in Inflammatory Diseases

Kano

Ong

Ori

et al. 2022

Front. Cell. Infect. Microbiol.

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Pattern recognition receptors (PRRs) play critical roles in recognizing pathogen-derived nucleic acids and inducing innate immune responses, such as inflammation and type I interferon production. PRRs that recognize nucleic acids include members of endosomal Toll-like receptors, cytosolic retinoic acid inducible gene I-like receptors, cyclic GMP–AMP synthase, absent in melanoma 2-like receptors, and nucleotide binding oligomerization domain-like receptors. Aberrant recognition of self-derived nucleic acids by these PRRs or unexpected activation of downstream signaling pathways results in the constitutive production of type I interferons and inflammatory cytokines, which lead to the development of autoimmune or autoinflammatory diseases. In this review, we focus on the nucleic acid-sensing machinery and its pathophysiological roles in various inflammatory diseases.

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Activation of Innate Immunity by Therapeutic Nucleic Acids

Cited by 24 publications

References 155 publications

Specificity of oligonucleotide gene therapy (OGT) agents

Specificity of oligonucleotide gene therapy (OGT) agents

The influence of chirality on the behavior of oligonucleotides inside cells: revealing the potent cytotoxicity of G-rich l-RNA

Pathophysiological Role of Nucleic Acid-Sensing Pattern Recognition Receptors in Inflammatory Diseases

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