Cut and Paste for Cancer Treatment: A DNA Nanodevice that Cuts Out an RNA Marker Sequence to Activate a Therapeutic Function

Molden, Tatiana A.; Niccum, Caitlyn T.; Kolpashchikov, Dmitry M.

doi:10.1002/ange.202006384

Cited by 2 publications

(2 citation statements)

References 29 publications

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“…The DNA machines use several short binding arms rather than one long (15-30 nt) monolith sequences, which is expected to have little or no nonspecific RNA binding when applied in cells. We demonstrated that the cancer maker can be cut out from the longer RNA marker sequence by using two additional Dz agents so that this shorter RNA product can be then used as an activator for cleavage of the targeted RNA 165 . Recently, the binary Dz technology was integrated into a rigid DNA nanostructure named 'Nanotweezer', which was used for cleavage of specific mRNA in living cells 166 , thus proving that this technology can be applied under intracellular conditions.…”

Section: Ribozymes and Deoxyribozymesmentioning

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: Ribozymes and Deoxyribozymesmentioning

confidence: 99%

Specificity of oligonucleotide gene therapy (OGT) agents

Nedorezova¹,

Dubovichenko²,

Belyaeva³

et al. 2022

Theranostics

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“…DNA oligonucleotides (ssDNA) are used as primers and probes in diagnostics, [1] biosensing, [2] and bioanalysis. [3] ssDNA is a material used by DNA nanotechnology for building nanostructures with shapes tailored to specific applications.…”

Section: Introductionmentioning

confidence: 99%

Designed assembly and disassembly of DNA in supramolecular structure: From ion regulated nuclear formation and machine learning recognition to running DNA cascade

et al. 2022

Self Cite

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In this paper, we introduce a novel encapsulation system for DNA oligonucleotides. Supramolecular assembly of melamine cyanurate encapsulates DNA at pH 7 and start to release it at pH less than 6.5. We study the assembly and disassembly in time in specially designed reaction-diffusion system. Magnesium ions allow spatial separation of DNA with the highest DNA concentration in the core of melamine cyanurate capsule. Molecular dynamics (MD) simulation shows that DNA acts as a nucleation centre for melamine cyanurate. Dataset of fluorescent images analysed by machine learning algorithms indicates correlation between structure of melamine cyanurate capsules for DNA trapping and concentration of magnesium ions. The concentration of magnesium ions can be recognized with 96% accuracy proving that all environmental conditions are extremely important during the self-assembly and should be considered for laboratory and industrial applications of the suggested approach. Moreover, the This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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Cut and Paste for Cancer Treatment: A DNA Nanodevice that Cuts Out an RNA Marker Sequence to Activate a Therapeutic Function

Cited by 2 publications

References 29 publications

Specificity of oligonucleotide gene therapy (OGT) agents

Specificity of oligonucleotide gene therapy (OGT) agents

Designed assembly and disassembly of DNA in supramolecular structure: From ion regulated nuclear formation and machine learning recognition to running DNA cascade

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