Conditional Antisense Oligonucleotides Triggered by miRNA

Zhang, Jiahui; Sharma, Radhika; Ryu, Kyungza; Shen, Patrick F.; Salaita, Khalid; Jo, Hanjoong

doi:10.1021/acschembio.1c00387

Cited by 8 publications

(8 citation statements)

References 42 publications

(55 reference statements)

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“…ASO-ND conjugates selective for HIF-1-α showed greater activity than that of the soluble ASO drug, without the use of transfection agents, and across a panel of three cell lines. The enhanced activity is likely to due to nuclease resistance, enhanced uptake, and improved bypass of endosomal entrapment and potentially due to multivalency which may boost affinity to its target . Importantly, ND can be engineered to deliver multiple cargos including miRNAs and siRNA as well as lipophilic molecules and peptides, and hence this platform may have broader applications as a therapeutic.…”

Section: Discussionmentioning

confidence: 99%

“…The enhanced activity is likely to due to nuclease resistance, enhanced uptake, and improved bypass of endosomal entrapment and potentially due to multivalency which may boost affinity to its target. 67 Importantly, ND can be engineered to deliver multiple cargos including miRNAs and siRNA as well as lipophilic molecules and peptides, and hence this platform may have broader applications as a therapeutic. Future work with ASO-NDs include expanded testing in other cell types, such as primary cells which may have different propensities for ND and ASO-ND uptake.…”

Section: ■ Conclusionmentioning

confidence: 99%

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Gene Regulation Using Nanodiscs Modified with HIF-1-α Antisense Oligonucleotides

Sharma

Dong

et al. 2022

Bioconjugate Chem.

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Delivery of nucleic acids can be hindered by multiple factors including nuclease susceptibility, endosome trapping, and clearance. Multiple nanotechnology scaffolds have offered promising solutions, and among these, lipid-based systems are advantageous because of their high biocompatibility and low toxicity. However, many lipid nanoparticle systems still have issues regarding stability, rapid clearance, and cargo leakage. Herein, we demonstrate the use of a synthetic nanodisc (ND) scaffold functionalized with an anti-HIF-1-α antisense oligonucleotide (ASO) to reduce HIF-1-α mRNA transcript levels. We prepared ND conjugates by using a mixture of phosphoglycerolipids with phosphocholine and phosphothioethanol headgroups that selfassemble into a ∼13 × 5 nm discoidal structure upon addition of a 22-amino-acid ApoA1 mimetic peptide. Optimized reaction conditions yield 15 copies of the anti-HIF-1-α ASO DNA covalently conjugated to the thiolated phospholipids using maleimide−thiol chemistry. We show that DNA-ND conjugates are active, nuclease resistant, and rapidly internalized into cells to regulate HIF-1-α mRNA levels without the use of transfection agents. DNA-ND uptake is partially mediated through Scavenger Receptor B1 and the ND conjugates show enhanced knockdown of HIF-1-α compared to that of the soluble ASOs in multiple cell lines. Our results demonstrate that covalently functionalized NDs may offer an improved platform for ASO therapeutics.

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Section: Discussionmentioning

confidence: 99%

Section: ■ Conclusionmentioning

confidence: 99%

Gene Regulation Using Nanodiscs Modified with HIF-1-α Antisense Oligonucleotides

Sharma

Dong

et al. 2022

Bioconjugate Chem.

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“…The translation can be either maintained or blocked by various pathways. [17,18] Biorender.com was used to prepare this Figure. In cis strategies to render mRNA light-responsive via modifications in the 5' UTR or throughout the sequence.…”

Section: Light-induced Gene Expression By Internal Mrna Modificationsmentioning

confidence: 99%

Optochemical Control of mRNA Translation in Eukaryotes

2023

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A major stage in the expression of genes is the translation of messenger RNA (mRNA), and the regulation of this process is essential for protein production in cells. How tightly controlled gene expression can be spatially and temporally, is particularly evident in polar cells and embryonic development. We need tools to dissect these complex processes, if we wish to understand the underlying links, especially the difficulties brought on by malfunction. External bioorthogonal triggers are very helpful in this area, if they let us precisely control where and when a process is started. Equipping nucleic acids with light-responsive groups has proven to be an effective approach to examine the dynamic regulatory route of mRNA translation in living cells. In this review, we present an overview of the most recent methods for optochemically controlling translation, focusing on cis-acting technologies.

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“…Nevertheless, due to its potential systemic side effects, EZN2968 is partially used in the clinic. For this reason, Zhang et al (2021) [ 107 ] proposed and generated a conditional ASO able to inhibit HIF-1alpha in cells expressing the target miRNA as a hepatocyte-specific miRNA, miR-122, via a toehold-exchange reaction [ 107 ].…”

Section: Potential Molecular Targets For Transcript-targeted Therapy ...mentioning

confidence: 99%

Transcript-Targeted Therapy Based on RNA Interference and Antisense Oligonucleotides: Current Applications and Novel Molecular Targets

Barresi

Musmeci

Rinaldi

et al. 2022

IJMS

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The development of novel target therapies based on the use of RNA interference (RNAi) and antisense oligonucleotides (ASOs) is growing in an exponential way, challenging the chance for the treatment of the genetic diseases and cancer by hitting selectively targeted RNA in a sequence-dependent manner. Multiple opportunities are taking shape, able to remove defective protein by silencing RNA (e.g., Inclisiran targets mRNA of protein PCSK9, permitting a longer half-life of LDL receptors in heterozygous familial hypercholesteremia), by arresting mRNA translation (i.e., Fomivirsen that binds to UL123-RNA and blocks the translation into IE2 protein in CMV-retinitis), or by reactivating modified functional protein (e.g., Eteplirsen able to restore a functional shorter dystrophin by skipping the exon 51 in Duchenne muscular dystrophy) or a not very functional protein. In this last case, the use of ASOs permits modifying the expression of specific proteins by modulating splicing of specific pre-RNAs (e.g., Nusinersen acts on the splicing of exon 7 in SMN2 mRNA normally not expressed; it is used for spinal muscular atrophy) or by downregulation of transcript levels (e.g., Inotersen acts on the transthryretin mRNA to reduce its expression; it is prescribed for the treatment of hereditary transthyretin amyloidosis) in order to restore the biochemical/physiological condition and ameliorate quality of life. In the era of precision medicine, recently, an experimental splice-modulating antisense oligonucleotide, Milasen, was designed and used to treat an 8-year-old girl affected by a rare, fatal, progressive form of neurodegenerative disease leading to death during adolescence. In this review, we summarize the main transcriptional therapeutic drugs approved to date for the treatment of genetic diseases by principal regulatory government agencies and recent clinical trials aimed at the treatment of cancer. Their mechanism of action, chemical structure, administration, and biomedical performance are predominantly discussed.

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Conditional Antisense Oligonucleotides Triggered by miRNA

Cited by 8 publications

References 42 publications

Gene Regulation Using Nanodiscs Modified with HIF-1-α Antisense Oligonucleotides

Gene Regulation Using Nanodiscs Modified with HIF-1-α Antisense Oligonucleotides

Optochemical Control of mRNA Translation in Eukaryotes

Transcript-Targeted Therapy Based on RNA Interference and Antisense Oligonucleotides: Current Applications and Novel Molecular Targets

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