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Oligonucleotides-A Novel Promising Therapeutic Option for IBD.
Front Pharmacol 2019; 10:314FP

Abstract

Inflammatory Bowel Diseases (IBD), whose denomination comprehends Crohn's Disease (CD) and Ulcerative Colitis (UC), are intestinal chronic diseases that often require lifelong medical therapy. In the last two decades monoclonal antibodies against the cytokine TNF have become integral parts in the treatment of IBD patients, however there are unwanted side-effects and one third of patients show primary non-response while another subgroup loses response over time. Finding novel drugs which could act as therapies against precise pro-inflammatory molecular targets to avoid unwanted systemic side effects and additionally the process of immunization, represents an important aim for subsequent therapeutic approaches. Oligonucleotide based therapies represent a promising novel concept for the treatment of IBD. The molecular action of oligonucleotides ranges from inhibition of the translational process of mRNA transcripts of pro-inflammatory molecules, to mimicking bacterial DNA which can activate cellular targets for immunomodulation. Alicaforsen, selectively targets ICAM-1 mRNA. ICAM-1 is an adhesion molecule which is upregulated on endothelial cells during IBD, thereby mediating the adhesion and migration of leucocytes from blood to sites of active inflammation. In CD parenteral application of alicaforsen did not show therapeutic efficacy in phase II trials, but it demonstrated an improved efficacy as a topical enema in distal UC. Topical application of alicaforsen might represent a therapeutic perspective for refractory pouchitis as well. SMAD7 is a protein that inhibits the signaling of TGFβ, which is the mainstay of a regulatory counterpart in cellular immune responses. An antisense oligonucleotide against SMAD7 mRNA (mongersen) demonstrated pre-clinical and phase II efficacy in CD, but a phase III clinical trial was stopped due to lack of efficacy. Cobitolimod is a single strand oligonucleotide, which mimics bacterial DNA as its CpG dinucleotide sequences can be recognized by the Toll-like receptor 9 on different immune cells thereby causing induction of different cytokines, for example IL10 and IFNα. Topical application of cobitolimod was studied in UC patients. We will also discuss two other novel oligonucleotides which act on the GATA3 transcription factor (SB012) and on carbohydrate sulfotransferase 15 (STNM01), which could both represent novel promising therapeutic options for the treatment of UC.

Authors+Show Affiliations

Department of Systems Medicine, Gastroenterology, University of Tor Vergata, Rome, Italy. Department of Medicine 1, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen, Germany.Department of Medicine 1, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen, Germany.Department of Systems Medicine, Gastroenterology, University of Tor Vergata, Rome, Italy.Department of Medicine 1, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen, Germany.Department of Medicine 1, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen, Germany.

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

31068803

Citation

Scarozza, Patrizio, et al. "Oligonucleotides-A Novel Promising Therapeutic Option for IBD." Frontiers in Pharmacology, vol. 10, 2019, p. 314.
Scarozza P, Schmitt H, Monteleone G, et al. Oligonucleotides-A Novel Promising Therapeutic Option for IBD. Front Pharmacol. 2019;10:314.
Scarozza, P., Schmitt, H., Monteleone, G., Neurath, M. F., & Atreya, R. (2019). Oligonucleotides-A Novel Promising Therapeutic Option for IBD. Frontiers in Pharmacology, 10, p. 314. doi:10.3389/fphar.2019.00314.
Scarozza P, et al. Oligonucleotides-A Novel Promising Therapeutic Option for IBD. Front Pharmacol. 2019;10:314. PubMed PMID: 31068803.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Oligonucleotides-A Novel Promising Therapeutic Option for IBD. AU - Scarozza,Patrizio, AU - Schmitt,Heike, AU - Monteleone,Giovanni, AU - Neurath,Markus F, AU - Atreya,Raja, Y1 - 2019/04/24/ PY - 2018/10/15/received PY - 2019/03/14/accepted PY - 2019/5/10/entrez PY - 2019/5/10/pubmed PY - 2019/5/10/medline KW - Crohn disease KW - IBD KW - antisense oligonucleotide (ASO) KW - target therapies KW - ulcerative colitis SP - 314 EP - 314 JF - Frontiers in pharmacology JO - Front Pharmacol VL - 10 N2 - Inflammatory Bowel Diseases (IBD), whose denomination comprehends Crohn's Disease (CD) and Ulcerative Colitis (UC), are intestinal chronic diseases that often require lifelong medical therapy. In the last two decades monoclonal antibodies against the cytokine TNF have become integral parts in the treatment of IBD patients, however there are unwanted side-effects and one third of patients show primary non-response while another subgroup loses response over time. Finding novel drugs which could act as therapies against precise pro-inflammatory molecular targets to avoid unwanted systemic side effects and additionally the process of immunization, represents an important aim for subsequent therapeutic approaches. Oligonucleotide based therapies represent a promising novel concept for the treatment of IBD. The molecular action of oligonucleotides ranges from inhibition of the translational process of mRNA transcripts of pro-inflammatory molecules, to mimicking bacterial DNA which can activate cellular targets for immunomodulation. Alicaforsen, selectively targets ICAM-1 mRNA. ICAM-1 is an adhesion molecule which is upregulated on endothelial cells during IBD, thereby mediating the adhesion and migration of leucocytes from blood to sites of active inflammation. In CD parenteral application of alicaforsen did not show therapeutic efficacy in phase II trials, but it demonstrated an improved efficacy as a topical enema in distal UC. Topical application of alicaforsen might represent a therapeutic perspective for refractory pouchitis as well. SMAD7 is a protein that inhibits the signaling of TGFβ, which is the mainstay of a regulatory counterpart in cellular immune responses. An antisense oligonucleotide against SMAD7 mRNA (mongersen) demonstrated pre-clinical and phase II efficacy in CD, but a phase III clinical trial was stopped due to lack of efficacy. Cobitolimod is a single strand oligonucleotide, which mimics bacterial DNA as its CpG dinucleotide sequences can be recognized by the Toll-like receptor 9 on different immune cells thereby causing induction of different cytokines, for example IL10 and IFNα. Topical application of cobitolimod was studied in UC patients. We will also discuss two other novel oligonucleotides which act on the GATA3 transcription factor (SB012) and on carbohydrate sulfotransferase 15 (STNM01), which could both represent novel promising therapeutic options for the treatment of UC. SN - 1663-9812 UR - https://www.unboundmedicine.com/medline/citation/31068803/Oligonucleotides_A_Novel_Promising_Therapeutic_Option_for_IBD_ L2 - https://dx.doi.org/10.3389/fphar.2019.00314 DB - PRIME DP - Unbound Medicine ER -