Ribonuclease H1-dependent hepatotoxicity caused by locked nucleic acid-modified gapmer antisense oligonucleotides

Kasuya, Tadashi; Hori, Shinichiro; Watanabe, Asako; Nakajima, Mado; Gahara, Yoshinari; Rokushima, Masatomo; Yanagimoto, Toru; Kugimiya, Akira

doi:10.1038/srep30377

Cited by 91 publications

(83 citation statements)

References 51 publications

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“…Gapmer ASOs bind not just to mRNA, but also to pre‐mRNA introns to cleave and degrade pre‐mRNA (Kamola et al, ; Kasuya et al, ). Thus, when searching for off‐target candidate genes of gapmer ASOs, an in silico analysis of a database that fully includes human pre‐mRNA should be conducted.…”

Section: Resultsmentioning

confidence: 99%

Evaluation of off‐target effects of gapmer antisense oligonucleotides using human cells

et al. 2019

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Antisense oligonucleotide (ASO) has the potential to induce off‐target effects due to complementary binding between the ASO and unintended RNA with a sequence similar to the target RNA. Conventional animal studies cannot be used to assess toxicity induced by off‐target effects because of differences in the genome sequence between humans and other animals. Consequently, the assessment of off‐target effects with in silico analysis using a human RNA database and/or in vitro expression analysis using human cells has been proposed.Our previous study showed that the number of complementary regions of ASOs with mismatches in the human RNA sequences increases dramatically as the number of tolerated mismatches increases. However, to what extent the expression of genes with mismatches is affected by off‐target effects at the cellular level is not clear. In this study, we evaluated off‐target effects of gapmer ASOs, which cleave the target RNA in an RNase H‐dependent manner, by introducing the ASO into human cells and performing microarray analysis. Our data indicate that gapmer ASOs induce off‐target effects depending on the degree of complementarity between the ASO and off‐target candidate genes. Based on our results, we also propose a scheme for the assessment of off‐target effects of gapmer ASOs.

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Section: Resultsmentioning

confidence: 99%

Evaluation of off‐target effects of gapmer antisense oligonucleotides using human cells

et al. 2019

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“…The risk of toxicity seems to apply equally to LNA and cEt, despite previous reports to the contrary, and is sequence-dependent. In the past year, three groups independently demonstrated that LNA and cEt gapmer ASOs induce liver toxicity by directing off-target RNase H cleavage of mismatched transcripts, particularly within introns 42-44 . Armed with this information, computational methods can be used to select ASOs with minimal complementarity to off-target transcripts (including introns).…”

Section: Chemical Evolution Of Asosmentioning

confidence: 99%

The chemical evolution of oligonucleotide therapies of clinical utility

2017

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After nearly 40 years of development, oligonucleotide therapeutics are nearing meaningful clinical productivity. One of the key advantages of oligonucleotide drugs is that their delivery and potency properties are derived primarily from the chemical structure of the oligonucleotide, while their target is defined by the base sequence. Thus, as oligonucleotides with a particular chemical design demonstrate appropriate distribution and safety profiles for clinical gene silencing in a particular tissue, this will open the door to the rapid development of additional drugs targeting other disease-associated genes in the same tissue. To achieve clinical productivity, the chemical architecture of the oligonucleotide needs to be optimized as a whole, using a combination of sugar, backbone, nucleobase and 3′/5′-terminal modifications. A portfolio of chemistries can be used to confer drug like properties onto the oligonucleotide as a whole, with minor chemical changes often translating into major improvements in clinical efficacy. Outstanding challenges in oligonucleotide chemical development include optimization of chemical architectures to ensure long-term safety and to enable robust clinical activity beyond the liver.

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“…GapmeR molecules, causes RNaseH-mediated gene silencing, independent of RNA-Induced Silencing Complex (RISC), and therefore, it does not cause RISC-associated or microRNA-like off-target activity. Because GapmeRs are short (13-20 nucleotides), off-target and mismatches have rarely occurred 14,26,27 . In the present study, we have been using antisense LNA GapmeRs to knock down lncRNA MIR100HG in acute promyelocytic This article can be downloaded from www.ijlpr.com L-18 leukemia (AML-M3) cell line (HL60).…”

Section: Discussionmentioning

confidence: 99%

The Effect of Inhibition of Lncrna Mir100hg on the Proliferation of Human Promyelocytic Leukemia Cells

Bagheri

Sharifi

Salehi

2019

Int J Life Sci Pharm Res

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lncRNAs are one of the main classes of non-coding RNAs, responsible for RNA regulation in a variety of cellular processes, and their effect on human cancer remains largely unexplored; Abnormal expression of lncRNAs has been shown to be associated with many human diseases and cancers, such as leukemia. Acute promyelocytic leukemia (APL) is the M3 subtype of acute myeloid leukemia (AML), with the aberrant accumulation of promyelocytes. One of the lncRNAs that showed upregulation in AML is lncRNA MIR100HG, involved in different cancers. The aim of our study is to investigate the functional role of MIR100HG antisense LNA GapmeRs, on APL cells. In this experimental study, we have used an Antisense LNA GapmeRs, in order to block MIR100HG in APL Cells. HL60 (APL cell line) cells were transfected with MIR100HG antisense LNA GapmeRs and at three different time points (24, 48 and 72 h) and were investigated apoptosis, necrosis, MIR100HG and TGFβ expression. MIR100HG inhibition could reduce the viability of HL-60 cells, through induction of apoptosis; because of the TGFβ upregulation. qRT-PCR was performed to determine the MIR100HG expression by antisense LNA GapmeRs. Our results suggest that degradation of MIR100HG could serve as a novel approach for controlling the proliferation of APL cells and therefore, can be used in translational medicine for targeted therapy in APL.

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Ribonuclease H1-dependent hepatotoxicity caused by locked nucleic acid-modified gapmer antisense oligonucleotides

Cited by 91 publications

References 51 publications

Evaluation of off‐target effects of gapmer antisense oligonucleotides using human cells

Evaluation of off‐target effects of gapmer antisense oligonucleotides using human cells

The chemical evolution of oligonucleotide therapies of clinical utility

The Effect of Inhibition of Lncrna Mir100hg on the Proliferation of Human Promyelocytic Leukemia Cells

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