ged0301 and Inflammatory-Bowel-Diseases

In the last decades, the better understanding of inflammatory bowel diseases (IBD) pathogenesis has contributed to the identification of new therapeutic targets that can be modulated to induce and maintain disease remission. Monoclonal antibodies against tumor necrosis factor, interleukin (IL)-12/IL-23p40, and the integrin α4β7 and inhibitors of Janus kinase molecules are valid compounds to limit the function of molecules implicated in the control of IBD-related inflammation. However, not all patients respond to treatment with such drugs, some of them lose response over time and others develop serious side effects, such as infections or malignancies, which lead to the discontinuation of the therapy. Thus, an intensive research is ongoing with the goal to identify new targets and develop novel therapeutic options. In this context, restoration of TGF-β activity and inhibition of phosphodiesterase 4 (PD4) represent two relevant strategies. TGF-β is an immunesuppressive cytokine, whose activity is severely impaired in IBD due to the abundance of the intracellular inhibitor Smad7. Knockdown of Smad7 with a specific antisense oligonucleotide restores TGF-β signalling and dampens effector immune responses in pre-clinical studies and initial clinical trials in Crohn's disease patients, even though a recent phase 3 trial was discontinued due to an apparent inefficacy. PD4 inhibition determines the increase of intracellular levels of cyclic adenosine monophosphate, a mechanism that decreases pro-inflammatory cytokine production. A recent phase 2 study has shown that oral administration of PD4 associates with clinical benefit in patients with ulcerative colitis. In this article, we review the rationale and the available data relative to the use of these two agents in IBD.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Humans; Inflammatory Bowel Diseases; Oligonucleotides; Phosphodiesterase 4 Inhibitors; Thalidomide; Thiazoles; Transforming Growth Factor beta

The growing understanding of the immunopathogenesis of inflammatory bowel diseases (IBDs) has contributed to the identification of new targets whose expression/activity can be modulated for therapeutic purposes. Several approaches have been employed to develop selective pharmaceutical compounds; among these, antisense oligonucleotides (ASOs) or synthetic oligonucleotides represent a valid option for inhibiting or enhancing, respectively, the expression/function of molecules that have been implicated in the control of IBD-related inflammation. In this context, data have been accumulated for the following compounds: alicaforsen, an ASO targeting intercellular adhesion molecule-1, a transmembrane glycoprotein that regulates rolling and adhesion of leukocytes to inflamed intestine; DIMS0150 and BL-7040, two oligonucleotides that enhance Toll-like receptor-9 activity; Mongersen, an ASO that inhibits Smad7, thereby restoring transforming growth factor-β1/Smad-associated signaling; STNM01, a double-stranded RNA oligonucleotide silencing carbohydrate sulfotransferase, an enzyme involved in fibrogenic processes, and hgd40, a specific DNAzyme inhibiting expression of the transcription factor GATA3. In this article, we review the rationale and the available data relative to the use of these agents in IBD. Although pre-clinical and phase II trials in IBD support the use of oligonucleotide-based therapies for treating the pathogenic process occurring in the gut of patients with these disorders, further work is needed to establish whether and which patients can benefit from specific ASOs and identify biomarkers that could help optimize treatment.

Topics: Clinical Trials as Topic; DNA; Genetic Therapy; Humans; Inflammatory Bowel Diseases; Intercellular Adhesion Molecule-1; Membrane Glycoproteins; Molecular Targeted Therapy; Oligonucleotides; Oligonucleotides, Antisense; Smad7 Protein; Sulfotransferases; Toll-Like Receptor 9; Transcription Factor RelA

The principal targets for anti-chemokine therapy in inflammatory bowel disease (IBD) have been the receptors CCR9 and CXCR3 and their respective ligands CCL25 and CXCL10. More recently CCR6 and its ligand CCL20 have also received attention, the expression of the latter in enterocytes being manipulated through Smad7 signalling. These pathways, selected based on their fundamental role in regulating mucosal immunity, have led to the development of several therapeutic candidates that have been tested in early phase clinical trials with variable clinical efficacy. In this article, we appraise the status of chemokine-directed therapy in IBD, review recent developments, and nominate future areas for therapeutic focus.

Topics: Animals; Antibodies, Monoclonal; Chemokine CCL20; Chemokine CXCL10; Chemokines; Chemokines, CC; Gastrointestinal Agents; Humans; Inflammatory Bowel Diseases; Molecular Targeted Therapy; Oligonucleotides; Receptors, CCR; Receptors, CCR6; Receptors, Chemokine; Receptors, CXCR3; Smad7 Protein; Sulfonamides

Insights into the pathogenesis of inflammatory bowel diseases (IBDs) have provided important information for the development of therapeutics. Levels of interleukin 23 (IL23) and T-helper (Th) 17 cell pathway molecules are increased in inflamed intestinal tissues of patients with IBD. Loss-of-function variants of the IL23-receptor gene (IL23R) protect against IBD, and, in animals, blocking IL23 reduces the severity of colitis. These findings indicated that the IL23 and Th17 cell pathways might be promising targets for the treatment of IBD. Clinical trials have investigated the effects of agents designed to target distinct levels of the IL23 and Th17 cell pathways, and the results are providing insights into IBD pathogenesis and additional strategies for modulating these pathways. Strategies to reduce levels of proinflammatory cytokines more broadly and increase anti-inflammatory mechanisms also are emerging for the treatment of IBD. The results from trials targeting these immune system pathways have provided important lessons for future trials. Findings indicate the importance of improving approaches to integrate patient features and biomarkers of response with selection of therapeutics.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Cytokines; Humans; Inflammatory Bowel Diseases; Interleukin-23; Janus Kinases; Lysophospholipids; Molecular Targeted Therapy; Oligonucleotides; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Signal Transduction; Smad7 Protein; Sphingosine; Th17 Cells; Transforming Growth Factor beta; Ustekinumab

Tumor necrosis factor (TNF) antagonists are the cornerstone of therapy for moderately to severely active inflammatory bowel disease (IBD). Although our understanding of pharmacokinetics, pharmacodynamics, and treatment optimization for these agents has evolved considerably over the past decade, a substantial majority of individuals fail to respond or lose response to TNF-antagonists over time. A need therefore remains for efficacious treatment options in these patients. Alternative immunological targets have now been identified, and several novel therapeutic agents are in development for IBD. In this review article, we discuss these novel therapeutic agents, with a particular focus on those demonstrated to be efficacious in phase 2 and 3 clinical trials. We further discuss considerations to be made when integrating these agents into routine practice over the next decade.

Topics: Antibodies, Monoclonal, Humanized; Biological Products; Cell Adhesion Molecules; Gastrointestinal Agents; Humans; Immunoglobulins; Indans; Inflammatory Bowel Diseases; Mucoproteins; Oligonucleotides; Oxadiazoles; Piperidines; Pyrimidines; Pyrroles; Tumor Necrosis Factor-alpha; Ustekinumab

Despite the great success of anti-tumour necrosis factor-based therapies, the treatment of Crohn's disease (CD) and ulcerative colitis (UC) still remains a challenge for clinicians, as these drugs are not effective in all patients, their efficacy may wane with time, and their use can increase the risk of adverse events and be associated with the development of new immune-mediated diseases. Therefore, new therapeutic targets are currently being investigated both in pre-clinical studies and in clinical trials. Among the technologies used to build new therapeutic compounds, the antisense oligonucleotide (ASO) approach is slowly gaining space in the field of inflammatory bowel diseases (IBDs), and three ASOs have been investigated in clinical trials. Systemic administration of alicaforsen targeting intercellular adhesion molecule-1, a protein involved in the recruitment of leukocytes to inflamed intestine, was not effective in CD, even though the same compound was of benefit when given as an enema to UC patients. DIMS0150, targeting nuclear factor (NF) κB-p65, a transcription factor that promotes pro-inflammatory responses, was very promising in pre-clinical studies and is currently being tested in clinical trials. Oral mongersen, targeting Smad7, an intracellular protein that inhibits transforming growth factor (TGF)-β1 activity, was safe and well tolerated by CD patients, and the results of a phase II clinical trial showed the efficacy of the drug in inducing clinical remission in patients with active disease. In this leading article, we review the rationale and the clinical data available regarding these three agents, and we discuss the challenge of using ASOs in IBD.

Topics: Animals; Clinical Trials as Topic; DNA; Humans; Inflammatory Bowel Diseases; Oligonucleotides; Oligonucleotides, Antisense; Phosphorothioate Oligonucleotides

Crohn's disease (CD) and ulcerative colitis (UC), two chronic and relapsing inflammatory bowel diseases (IBD), are supposed to develop in genetically-predisposed individuals as a result of an excessive immune mucosal response directed against normal components of the gut microbiota. There is also evidence that defects in counter-regulatory mechanisms play a major role in the pathogenesis of IBD. One such a defect involves TGF-β1, a cytokine produced by multiple cells types and able to inhibit pathogenic responses in the gut. In both CD and UC, TGF-β1 is highly produced but unable to signal through the TGF-β receptor-associated Smad pathway and suppress production of inflammatory molecules. Abrogation of TGF-β1 activity has been related to Smad7, an intracellular protein that binds to TGF-β receptor and inhibits TGF-β1-driven Smad-dependent signalling. Indeed, silencing of Smad7 with a specific antisense oligonucleotide restores TGF-β1/Smad signalling, thereby down-regulating inflammatory cytokine production and ameliorating experimental colitis in mice. Altogether these observations led to the development of an oral pharmaceutical compound containing the specific Smad7 antisense oligonucleotide (herein termed GED0301), which seems to be safe and well tolerated in CD patients. In this article we summarize the data supporting the pathogenic role of Smad7 in IBD and discuss the recent results of the use of GED0301 in CD.

Topics: Animals; Clinical Trials, Phase I as Topic; Colitis, Ulcerative; Crohn Disease; Gene Expression Regulation; Humans; Inflammatory Bowel Diseases; Mice; Oligonucleotides; Oligonucleotides, Antisense; Receptors, Transforming Growth Factor beta; Signal Transduction; Smad7 Protein; Transforming Growth Factor beta