Effect of Native Gastric Mucus on in vivo Hybridization Therapies Directed at Helicobacter pylori

Rita S Santos, George R Dakwar, Ranhua Xiong, Katrien Forier, Katrien Remaut, Stephan Stremersch, Nuno Guimarães, Sílvia Fontenete, Jesper Wengel, Marina Leite, Céu Figueiredo, Stefaan C De Smedt, Kevin Braeckmans, Nuno F Azevedo

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Abstract

Helicobacter pylori infects more than 50% of the worldwide population. It is mostly found deep in the gastric mucus lining of the stomach, being a major cause of peptic ulcers and gastric adenocarcinoma. To face the increasing resistance of H. pylori to antibiotics, antimicrobial nucleic acid mimics are a promising alternative. In particular, locked nucleic acids (LNA)/2'-OMethyl RNA (2'OMe) have shown to specifically target H. pylori, as evidenced by in situ hybridization. The success of in vivo hybridization depends on the ability of these nucleic acids to penetrate the major physical barriers-the highly viscoelastic gastric mucus and the bacterial cell envelope. We found that LNA/2'OMe is capable of diffusing rapidly through native, undiluted, gastric mucus isolated from porcine stomachs, without degradation. Moreover, although LNA/2'OMe hybridization was still successful without permeabilization and fixation of the bacteria, which is normally part of in vitro studies, the ability of LNA/2'OMe to efficiently hybridize with H. pylori was hampered by the presence of mucus. Future research should focus on developing nanocarriers that shield LNA/2'OMe from components in the gastric mucus, while remaining capable of diffusing through the mucus and delivering these nucleic acid mimics directly into the bacteria.

Original languageEnglish
JournalMolecular Therapy - Nucleic Acids
Volume4
Pages (from-to)e269
Number of pages9
ISSN2162-2531
DOIs
Publication statusPublished - 10. Dec 2015

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Mucus
Helicobacter pylori
RNA
Nucleic Acids
Population

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Santos, R. S., Dakwar, G. R., Xiong, R., Forier, K., Remaut, K., Stremersch, S., ... Azevedo, N. F. (2015). Effect of Native Gastric Mucus on in vivo Hybridization Therapies Directed at Helicobacter pylori. Molecular Therapy - Nucleic Acids, 4, e269. https://doi.org/10.1038/mtna.2015.46
Santos, Rita S ; Dakwar, George R ; Xiong, Ranhua ; Forier, Katrien ; Remaut, Katrien ; Stremersch, Stephan ; Guimarães, Nuno ; Fontenete, Sílvia ; Wengel, Jesper ; Leite, Marina ; Figueiredo, Céu ; De Smedt, Stefaan C ; Braeckmans, Kevin ; Azevedo, Nuno F. / Effect of Native Gastric Mucus on in vivo Hybridization Therapies Directed at Helicobacter pylori. In: Molecular Therapy - Nucleic Acids. 2015 ; Vol. 4. pp. e269.
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abstract = "Helicobacter pylori infects more than 50{\%} of the worldwide population. It is mostly found deep in the gastric mucus lining of the stomach, being a major cause of peptic ulcers and gastric adenocarcinoma. To face the increasing resistance of H. pylori to antibiotics, antimicrobial nucleic acid mimics are a promising alternative. In particular, locked nucleic acids (LNA)/2'-OMethyl RNA (2'OMe) have shown to specifically target H. pylori, as evidenced by in situ hybridization. The success of in vivo hybridization depends on the ability of these nucleic acids to penetrate the major physical barriers-the highly viscoelastic gastric mucus and the bacterial cell envelope. We found that LNA/2'OMe is capable of diffusing rapidly through native, undiluted, gastric mucus isolated from porcine stomachs, without degradation. Moreover, although LNA/2'OMe hybridization was still successful without permeabilization and fixation of the bacteria, which is normally part of in vitro studies, the ability of LNA/2'OMe to efficiently hybridize with H. pylori was hampered by the presence of mucus. Future research should focus on developing nanocarriers that shield LNA/2'OMe from components in the gastric mucus, while remaining capable of diffusing through the mucus and delivering these nucleic acid mimics directly into the bacteria.",
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Santos, RS, Dakwar, GR, Xiong, R, Forier, K, Remaut, K, Stremersch, S, Guimarães, N, Fontenete, S, Wengel, J, Leite, M, Figueiredo, C, De Smedt, SC, Braeckmans, K & Azevedo, NF 2015, 'Effect of Native Gastric Mucus on in vivo Hybridization Therapies Directed at Helicobacter pylori', Molecular Therapy - Nucleic Acids, vol. 4, pp. e269. https://doi.org/10.1038/mtna.2015.46

Effect of Native Gastric Mucus on in vivo Hybridization Therapies Directed at Helicobacter pylori. / Santos, Rita S; Dakwar, George R; Xiong, Ranhua; Forier, Katrien; Remaut, Katrien; Stremersch, Stephan; Guimarães, Nuno; Fontenete, Sílvia; Wengel, Jesper; Leite, Marina; Figueiredo, Céu; De Smedt, Stefaan C; Braeckmans, Kevin; Azevedo, Nuno F.

In: Molecular Therapy - Nucleic Acids, Vol. 4, 10.12.2015, p. e269.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - Effect of Native Gastric Mucus on in vivo Hybridization Therapies Directed at Helicobacter pylori

AU - Santos, Rita S

AU - Dakwar, George R

AU - Xiong, Ranhua

AU - Forier, Katrien

AU - Remaut, Katrien

AU - Stremersch, Stephan

AU - Guimarães, Nuno

AU - Fontenete, Sílvia

AU - Wengel, Jesper

AU - Leite, Marina

AU - Figueiredo, Céu

AU - De Smedt, Stefaan C

AU - Braeckmans, Kevin

AU - Azevedo, Nuno F

PY - 2015/12/10

Y1 - 2015/12/10

N2 - Helicobacter pylori infects more than 50% of the worldwide population. It is mostly found deep in the gastric mucus lining of the stomach, being a major cause of peptic ulcers and gastric adenocarcinoma. To face the increasing resistance of H. pylori to antibiotics, antimicrobial nucleic acid mimics are a promising alternative. In particular, locked nucleic acids (LNA)/2'-OMethyl RNA (2'OMe) have shown to specifically target H. pylori, as evidenced by in situ hybridization. The success of in vivo hybridization depends on the ability of these nucleic acids to penetrate the major physical barriers-the highly viscoelastic gastric mucus and the bacterial cell envelope. We found that LNA/2'OMe is capable of diffusing rapidly through native, undiluted, gastric mucus isolated from porcine stomachs, without degradation. Moreover, although LNA/2'OMe hybridization was still successful without permeabilization and fixation of the bacteria, which is normally part of in vitro studies, the ability of LNA/2'OMe to efficiently hybridize with H. pylori was hampered by the presence of mucus. Future research should focus on developing nanocarriers that shield LNA/2'OMe from components in the gastric mucus, while remaining capable of diffusing through the mucus and delivering these nucleic acid mimics directly into the bacteria.

AB - Helicobacter pylori infects more than 50% of the worldwide population. It is mostly found deep in the gastric mucus lining of the stomach, being a major cause of peptic ulcers and gastric adenocarcinoma. To face the increasing resistance of H. pylori to antibiotics, antimicrobial nucleic acid mimics are a promising alternative. In particular, locked nucleic acids (LNA)/2'-OMethyl RNA (2'OMe) have shown to specifically target H. pylori, as evidenced by in situ hybridization. The success of in vivo hybridization depends on the ability of these nucleic acids to penetrate the major physical barriers-the highly viscoelastic gastric mucus and the bacterial cell envelope. We found that LNA/2'OMe is capable of diffusing rapidly through native, undiluted, gastric mucus isolated from porcine stomachs, without degradation. Moreover, although LNA/2'OMe hybridization was still successful without permeabilization and fixation of the bacteria, which is normally part of in vitro studies, the ability of LNA/2'OMe to efficiently hybridize with H. pylori was hampered by the presence of mucus. Future research should focus on developing nanocarriers that shield LNA/2'OMe from components in the gastric mucus, while remaining capable of diffusing through the mucus and delivering these nucleic acid mimics directly into the bacteria.

U2 - 10.1038/mtna.2015.46

DO - 10.1038/mtna.2015.46

M3 - Journal article

C2 - 26645765

VL - 4

SP - e269

JO - Molecular Therapy - Nucleic Acids

JF - Molecular Therapy - Nucleic Acids

SN - 2162-2531

ER -