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.
Highlights
Inflammatory bowel diseases (IBD) are chronic inflammatory disorders of the intestine whose phenotypic spectrum mainly comprehends Crohn’s disease (CD) and ulcerative colitis (UC)
This review focuses on pharmacodynamics and clinical perspectives of oligonucleotide based therapeutics so far studied for the treatment of IBD. (Supplementary Material)
The study evidenced the safety of the drug and reduced the segmental Simple Endoscopic Score for Crohn’s disease (SES-CD) score
Summary
Inflammatory bowel diseases (IBD) are chronic inflammatory disorders of the intestine whose phenotypic spectrum mainly comprehends Crohn’s disease (CD) and ulcerative colitis (UC). IBD patients often require treatment with immunomodulatory drugs such as thiopurines, methotrexate; biological drugs, like anti-Tumor Necrosing Factor (anti-TNF), anti-adhesion, or anti-interleukin 12/23p40 (IL12/23p40) antibodies and lately Janus Kinase Inhibitors (JAKinhibitors). These different substance classes have become integral parts in the treatment of IBD patients; there are unwanted, sometimes even severe side effects and over one third of patients show primary non-response while another subgroup of patients loses response over time (Roda et al, 2016). Oligonucleotides represent an emerging substance class of targeted therapies with only limited systemic exposure to the drug, giving hope for a novel and rather safe treatment modality in IBD
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