Nucleobase-modified antisense oligonucleotides containing 5-(phenyltriazol)-2′-deoxyuridine nucleotides induce exon-skipping

In vitro

Bao T. Le, Mick Hornum, Pawan K. Sharma, Poul Nielsen, Rakesh N. Veedu*

*Kontaktforfatter for dette arbejde

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Resumé

Chemically-modified antisense oligonucleotide-mediated exon-skipping has been validated as a therapeutic strategy for tackling several disease pathologies, particularly duchenne muscular dystrophy. To date, only sugar-modified and internucleotide linkage-modified oligonucleotide chemistries have been explored for exon-skipping applications. Herein, for the first time, we have investigated the potential of nucleobase-modified antisense oligonucleotides to induce exon-skipping. For this purpose, we have synthesised 5-(phenyltriazol)-2′-deoxyuridine-modified 2′-O-methyl mixmer antisense oligonucleotides, and evaluated their efficacy to induce exon-23 skipping in H-2Kb-tsA58 (H2K) mdx mouse myotubes as a model system. Our results showed that the phenyltriazol base-modified AOs successfully induced efficient exon-skipping in a DMD transcript. Our findings open up the exploration of novel base-modified antisense oligonucleotides for exon-skipping applications.

OriginalsprogEngelsk
TidsskriftRSC Advances
Vol/bind7
Udgave nummer86
Sider (fra-til)54542-54545
ISSN2046-2069
DOI
StatusUdgivet - 2017

Fingeraftryk

Deoxyuridine
Antisense Oligonucleotides
Oligonucleotides
Nucleotides
Exons
Pathology
Sugars

Citer dette

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title = "Nucleobase-modified antisense oligonucleotides containing 5-(phenyltriazol)-2′-deoxyuridine nucleotides induce exon-skipping: In vitro",
abstract = "Chemically-modified antisense oligonucleotide-mediated exon-skipping has been validated as a therapeutic strategy for tackling several disease pathologies, particularly duchenne muscular dystrophy. To date, only sugar-modified and internucleotide linkage-modified oligonucleotide chemistries have been explored for exon-skipping applications. Herein, for the first time, we have investigated the potential of nucleobase-modified antisense oligonucleotides to induce exon-skipping. For this purpose, we have synthesised 5-(phenyltriazol)-2′-deoxyuridine-modified 2′-O-methyl mixmer antisense oligonucleotides, and evaluated their efficacy to induce exon-23 skipping in H-2Kb-tsA58 (H2K) mdx mouse myotubes as a model system. Our results showed that the phenyltriazol base-modified AOs successfully induced efficient exon-skipping in a DMD transcript. Our findings open up the exploration of novel base-modified antisense oligonucleotides for exon-skipping applications.",
author = "Le, {Bao T.} and Mick Hornum and Sharma, {Pawan K.} and Poul Nielsen and Veedu, {Rakesh N.}",
year = "2017",
doi = "10.1039/c7ra10964d",
language = "English",
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pages = "54542--54545",
journal = "R S C Advances",
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Nucleobase-modified antisense oligonucleotides containing 5-(phenyltriazol)-2′-deoxyuridine nucleotides induce exon-skipping : In vitro. / Le, Bao T.; Hornum, Mick; Sharma, Pawan K.; Nielsen, Poul; Veedu, Rakesh N.

I: RSC Advances, Bind 7, Nr. 86, 2017, s. 54542-54545.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Nucleobase-modified antisense oligonucleotides containing 5-(phenyltriazol)-2′-deoxyuridine nucleotides induce exon-skipping

T2 - In vitro

AU - Le, Bao T.

AU - Hornum, Mick

AU - Sharma, Pawan K.

AU - Nielsen, Poul

AU - Veedu, Rakesh N.

PY - 2017

Y1 - 2017

N2 - Chemically-modified antisense oligonucleotide-mediated exon-skipping has been validated as a therapeutic strategy for tackling several disease pathologies, particularly duchenne muscular dystrophy. To date, only sugar-modified and internucleotide linkage-modified oligonucleotide chemistries have been explored for exon-skipping applications. Herein, for the first time, we have investigated the potential of nucleobase-modified antisense oligonucleotides to induce exon-skipping. For this purpose, we have synthesised 5-(phenyltriazol)-2′-deoxyuridine-modified 2′-O-methyl mixmer antisense oligonucleotides, and evaluated their efficacy to induce exon-23 skipping in H-2Kb-tsA58 (H2K) mdx mouse myotubes as a model system. Our results showed that the phenyltriazol base-modified AOs successfully induced efficient exon-skipping in a DMD transcript. Our findings open up the exploration of novel base-modified antisense oligonucleotides for exon-skipping applications.

AB - Chemically-modified antisense oligonucleotide-mediated exon-skipping has been validated as a therapeutic strategy for tackling several disease pathologies, particularly duchenne muscular dystrophy. To date, only sugar-modified and internucleotide linkage-modified oligonucleotide chemistries have been explored for exon-skipping applications. Herein, for the first time, we have investigated the potential of nucleobase-modified antisense oligonucleotides to induce exon-skipping. For this purpose, we have synthesised 5-(phenyltriazol)-2′-deoxyuridine-modified 2′-O-methyl mixmer antisense oligonucleotides, and evaluated their efficacy to induce exon-23 skipping in H-2Kb-tsA58 (H2K) mdx mouse myotubes as a model system. Our results showed that the phenyltriazol base-modified AOs successfully induced efficient exon-skipping in a DMD transcript. Our findings open up the exploration of novel base-modified antisense oligonucleotides for exon-skipping applications.

U2 - 10.1039/c7ra10964d

DO - 10.1039/c7ra10964d

M3 - Journal article

VL - 7

SP - 54542

EP - 54545

JO - R S C Advances

JF - R S C Advances

SN - 2046-2069

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