Oligonucleotides—A Novel Promising Therapeutic Option for IBD

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.

Phytochemical Regulation of RNA in Treating Inflammatory Bowel Disease and Colon Cancer: Inspirations from Cell and Animal Studies

“…Therefore, upstream regulation of undruggable targets could be a more effective choice. Antisense oligonucleotides (ASOs) and RNAi strategies targeting RNA have been clinically tested in the treatment of IBD and colon cancer with preliminary results showing great potential (Scarozza et al, 2019). Because the advantages of small molecule drugs in absorption, distribution and oral bioavailability This article has not been copyedited and formatted.…”

“…Although it is not confirmed that regulating RNA is the main mechanisms underlying these phytochemical-induced treatment effects, a preclinical study has RNA-based treatments of IBD/colon cancer by small molecule drugs also come with many problems, such as toxicity, lack of tissue-specific targeting, and drug failure (Rupaimoole and Slack, 2017). The performance of RNA-based ASOs for drugs entering clinical trials is not always optimal (Scarozza et al, 2019;Liu and Guo, 2020). Alicaforsen is a phosphorothioate ASO that can hybridize with vascular cell adhesion molecule 1 mRNA and induce DNA-RNA complex degradation by the This article has not been copyedited and formatted.…”

Emerging Treatment Options in Inflammatory Bowel Disease: Janus Kinases, Stem Cells, and More

“…Specific inactivation of selected genes involved in disease pathogenesis has been the dream of drug developers. When delivered into the cytoplasm, small RNA oligonucleotides will find the specific complementary mRNA of a target gene and activate the enzyme RNase H, resulting in degradation of the respective mRNA [87, 88]. Therefore, oligonucleotide therapeutics offer the possible advantage for the selective downregulation of a selected gene with potentially fewer side effects.…”

“…Mongersen is a chemically stabilized oligonucleotide directed against Smad7 and contains cytidine-phosphate-guanosine motives to avoid immune activation (see below). Mongersen is an oral drug, formulated for preferential release in the terminal ileum and right-sided colon for optimal treatment of CD [87, 88]. However, even though phase II studies showed high rates of clinical remission (65 vs. 10% with placebo) [89, 90], a recent large-scale phase III study was stopped due to lack of efficacy, and it remains unclear whether mongersen will ever be applied clinically [91].…”

Current perspectives on inhibitory SMAD7 in health and disease

“…For the better part of two decades, the scientific community has followed the development of AON treatment in various diseases, including IBD (Scarozza et al 2019). It was reported that SMAD7 AON treatment could potentially restore the endogenous TGF-b signaling pathway and attenuate IBD (Boirivant et al 2006).…”