Autoimmunity – High-Specificity Targets
Examining the role of IL-23 in autoimmune diseases and developing targeted antagonists for protein-based therapies
Inflammatory bowel diseases (IBDs) such as Crohn’s disease and ulcerative colitis represent aberrant or dysregulated immune responses of the gastrointestinal tract, which lead to a state of chronic inflammation. These diseases, which affect more than 1.4 million Americans, are now known to involve variants of a number of different genes, and the standard treatments frequently involve aggressive systemic wide steroids that cause liver damage and sensitization following long-term use. Understanding the molecular pathways involved in these autoimmune diseases will allow more targeted treatments to be developed.
Previous genetic studies uncovered a link between Crohn's and variants of the gene CARD15 (also known as NOD2), but this gene plays a role in only some Crohn's patients, and does not affect the risk for colitis. Recent discovery has linked the gene encoding for interleukin-23 (IL-23) receptor with the development of Crohn’s, and it is believed that IL-23 has a much larger effect on these inflammatory diseases, and affects risk for both Crohn's and colitis. However, how IL-23 initiates intestinal inflammation remains unclear, a point central to the work conducted by Dr. Oukka and his team. To understand the role of IL-23 in IBDs, Dr. Oukka’s team has generated a new mouse model in which the gene encoding for the Green Fluorescent Protein has been knocked-in in the endogenous IL-23R gene locus, using the method of homologous recombination in ES cells. They believe that this mouse will help precisely discern the immune mechanisms involved in chronic inflammatory diseases and identify subsets of cells involved in this pathology. Additionally, this mouse could be used to screen for drugs and treatments that turn off IL-23R expression in the intestine in the near future.
Work conducted by Dr. Oukka and his team also focuses on developing novel protein therapies for Multiple Sclerosis and Crohn’s Disease by applying computational design to create de novo cytokine antagonists. While current experimental treatments for these diseases involve producing monoclonal antibodies (mAbs) that target IL-17 and IL-23, they bear challenges in their bio-distribution, stability, and cost of production. Dr Oukka’s group specifically aims to test whether stable IL-23 cytokine antagonists with favorable bio-distribution can be used as a highly targeted treatment for autoimmunity. Furthermore, Dr. Oukka wishes to emphasize the development of compounds through computational biology that are stable enough for oral ingestion as a preferred delivery method for pediatric patients, and reduce systemic interactions that are seen with injectable autoimmune therapies. Dr. Oukka and his team are interested in collaborating with industry partners on these types of projects, with evaluation of effectiveness and safety being aided by their novel IL-23 mouse model.
Stage of Development
- Pre-clinical in vitro
- Pre-clinical in vivo
- Pre-clinical in silico
- Collaborative research opportunity
- Development opportunity
- Sponsored research agreement
- Consultation agreement
- Collaborative animal model development
- Eken A, Singh A, Oukka M. Interleukin 23 in Crohn's disease. Inflamm Bowel Dis. 2014;20(3):587-595.
- Eken A, Singh A, Treuting P, Oukka M. IL-23R+ innate lymphoid cells induce colitis via interleukin-22-dependent mechanism. Mucosal Immunol. 2013;7(1):143-154.
- Kyttaris V, Zhang Z, Kuchroo V, Oukka M, Tsokos G. Cutting Edge: IL-23 Receptor Deficiency Prevents the Development of Lupus Nephritis in C57BL/6-lpr/lpr Mice. The Journal of Immunology. 2010;184(9):4605-4609.
- Awasthi A, Riol-Blanco L, Jager A et al. Cutting Edge: IL-23 Receptor GFP Reporter Mice Reveal Distinct Populations of IL-17-Producing Cells. The Journal of Immunology. 2009;182(10):5904-5908.
- Bettelli E, Korn T, Oukka M, Kuchroo V. Induction and effector functions of TH17 cells. Nature. 2008;453(7198):1051-1057.
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