Chemical modification of PS-ASO therapeutics reduces cellular protein-binding and improves the therapeutic index

Shen, Wen‐Hui; Hoyos, Cheryl Li De; Migawa, Michael T.; Vickers, Timothy A.; Sun, Hong; Low, Audrey; Bell, Thomas A.; Rahdar, Meghdad; Mukhopadhyay, Swagatam; Hart, Christopher E.; Bell, Melanie; Riney, Stan; Murray, Susan F.; Greenlee, Sarah; Crooke, Rosanne M.; Liang, Xiaojing; Seth, Punit P.; Crooke, Stanley T.

doi:10.1038/s41587-019-0106-2

Cited by 222 publications

(270 citation statements)

References 47 publications

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“…However, toxic PS-ASOs were described, which are able to bind directly to RNase H and serve as a competitive inhibitor. These data indicate that toxic single-stranded PS-ASOs can associate with RNase H and induce RNase H degradation [32]. Therefore, the so called 'gapmer design' was established to enhance RNase H activity by a central stretch of DNA or phosphorothioate oligomers (PTO) / PS DNA monomers and flanking LNA ends, increasing stability and selectivity.…”

Section: Discussionmentioning

confidence: 99%

Antisense Oligonucleotide in LNA-Gapmer Design Targeting TGFBR2—A Key Single Gene Target for Safe and Effective Inhibition of TGFβ Signaling

Kuespert

Heydn

Peters

et al. 2020

IJMS

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Antisense Oligonucleotides (ASOs) are an emerging drug class in gene modification. In our study we developed a safe, stable, and effective ASO drug candidate in locked nucleic acid (LNA)-gapmer design, targeting TGFβ receptor II (TGFBR2) mRNA. Discovery was performed as a process using state-of-the-art library development and screening. We intended to identify a drug candidate optimized for clinical development, therefore human specificity and gymnotic delivery were favored by design. A staggered process was implemented spanning in-silico-design, in-vitro transfection, and in-vitro gymnotic delivery of small batch syntheses. Primary in-vitro and in-vivo toxicity studies and modification of pre-lead candidates were also part of this selection process. The resulting lead compound NVP-13 unites human specificity and highest efficacy with lowest toxicity. We particularly focused at attenuation of TGFβ signaling, addressing both safety and efficacy. Hence, developing a treatment to potentially recondition numerous pathological processes mediated by elevated TGFβ signaling, we have chosen to create our data in human lung cell lines and human neuronal stem cell lines, each representative for prospective drug developments in pulmonary fibrosis and neurodegeneration. We show that TGFBR2 mRNA as a single gene target for NVP-13 responds well, and that it bears great potential to be safe and efficient in TGFβ signaling related disorders.

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Section: Discussionmentioning

confidence: 99%

Antisense Oligonucleotide in LNA-Gapmer Design Targeting TGFBR2—A Key Single Gene Target for Safe and Effective Inhibition of TGFβ Signaling

Kuespert

Heydn

Peters

et al. 2020

IJMS

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“…However, both miRNA mimics and inhibitors are naturally subjected to degradation by nucleases [92]; chemical modifications are needed in order to be used for in vivo therapies. Several modifications have been described to counteract nucleases degradation, such as 2 -O-methyl, cholesterol tail and phosphorothioate [93,94].…”

Section: Mirna Mimicking or Inhibitionmentioning

confidence: 99%

Targeting microRNAs as a Therapeutic Strategy to Reduce Oxidative Stress in Diabetes

Grieco

Brusco

Licata

et al. 2019

IJMS

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Diabetes mellitus is a group of heterogeneous metabolic disorders characterized by chronic hyperglycaemia as a consequence of pancreatic β cell loss and/or dysfunction, also caused by oxidative stress. The molecular mechanisms involved inβ cell dysfunction and in response to oxidative stress are also regulated by microRNAs (miRNAs). miRNAs are a class of negative gene regulators, which modulate pathologic mechanisms occurring in diabetes and its complications. Although several pharmacological therapies specifically targeting miRNAs have already been developed and brought to the clinic, most previous miRNA-based drug delivery methods were unable to target a specific miRNA in a single cell type or tissue, leading to important off-target effects. In order to overcome these issues, aptamers and nanoparticles have been described as non-cytotoxic vehicles for miRNA-based drug delivery. These approaches could represent an innovative way to specifically target and modulate miRNAs involved in oxidative stress in diabetes and its complications. Therefore, the aims of this review are: (i) to report the role of miRNAs involved in oxidative stress in diabetes as promising therapeutic targets; (ii) to shed light onto the new delivery strategies developed to modulate the expression of miRNAs in diseases.

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“…The initial goal was to ensure minimal nuclease activity with sequences and then ensure sufficient target affinity. For ASO applications, these studies narrowly focused on defining nucleic acid functionality by its endpoint ability to bind to the oligonucleotide target (e.g., mRNA) itself; however, a series of recent publications by Crooke and colleagues [ 64 , 65 , 66 ] examines the importance of specifically understanding the role of ASO interactions with other proteins encountered on its pathway to the desired oligonucleotide target. As just one example, in addition to rendering the P atom as a chiral center in the phosphate group, the sulfur atom substitution in PS reportedly “spreads” the negative charge and makes the phosphate group itself more lipophilic [ 67 ].…”

Section: General Introductionmentioning

confidence: 99%

Modified Nucleic Acids: Expanding the Capabilities of Functional Oligonucleotides

Ochoa

Milam

2020

Molecules

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In the last three decades, oligonucleotides have been extensively investigated as probes, molecular ligands and even catalysts within therapeutic and diagnostic applications. The narrow chemical repertoire of natural nucleic acids, however, imposes restrictions on the functional scope of oligonucleotides. Initial efforts to overcome this deficiency in chemical diversity included conservative modifications to the sugar-phosphate backbone or the pendant base groups and resulted in enhanced in vivo performance. More importantly, later work involving other modifications led to the realization of new functional characteristics beyond initial intended therapeutic and diagnostic prospects. These results have inspired the exploration of increasingly exotic chemistries highly divergent from the canonical nucleic acid chemical structure that possess unnatural physiochemical properties. In this review, the authors highlight recent developments in modified oligonucleotides and the thrust towards designing novel nucleic acid-based ligands and catalysts with specifically engineered functions inaccessible to natural oligonucleotides.

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Chemical modification of PS-ASO therapeutics reduces cellular protein-binding and improves the therapeutic index

Cited by 222 publications

References 47 publications

Antisense Oligonucleotide in LNA-Gapmer Design Targeting TGFBR2—A Key Single Gene Target for Safe and Effective Inhibition of TGFβ Signaling

Antisense Oligonucleotide in LNA-Gapmer Design Targeting TGFBR2—A Key Single Gene Target for Safe and Effective Inhibition of TGFβ Signaling

Targeting microRNAs as a Therapeutic Strategy to Reduce Oxidative Stress in Diabetes

Modified Nucleic Acids: Expanding the Capabilities of Functional Oligonucleotides

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