Humanized IL-36R Rodent Model for Accurate DITRA Signaling
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Solution Overview
Problem
Existing models fail to accurately replicate the enhanced IL-36R signaling observed in DITRA patients, limiting the development of effective therapeutic agents for conditions associated with deregulated IL-36 signaling such as psoriasis and inflammatory bowel disease.
Innovation Solution
Genetically modify rodents with a humanized Il1rl2 gene and human IL-36α, β, and γ ligand genes, maintaining the endogenous IL-36Ra antagonist, which is 20-fold less potent, to create a model that mimics DITRA symptoms, allowing for the study of these diseases and testing therapeutic agents.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing animal models are used to study DITRA disease, then research can proceed with available models, but the models fail to accurately replicate the enhanced IL-36R signaling observed in DITRA patients
Solution Approach 1:
The patent applies parameter changes by modifying the rodent genome to include humanized Il1rl2 and human IL-36 ligand genes, thereby changing the signaling parameters to replicate human DITRA disease pathology. This creates a model where IL-36R signaling is enhanced to match patient conditions, resolving the contradiction between model accuracy and therapeutic suitability.
Solution Approach 2:
The patent uses humanized Il1rl2 and human IL-36 ligand genes as intermediaries to bridge the gap between rodent models and human disease. These genetic elements mediate the signaling pathway to accurately replicate DITRA pathology while maintaining the rodent model system, enabling both accurate disease replication and therapeutic testing.
2Reliability
If rodent models are genetically modified with humanized genes, then accurate DITRA modeling is achieved, but the complexity of model creation increases
Solution Approach 1:
The patent applies segmentation by dividing the genetic modification into distinct components: humanized Il1rl2 gene modification and human IL-36 ligand gene introduction. This segmented approach allows systematic creation of the disease model while maintaining clarity in the genetic architecture, managing the complexity through structured genetic elements.
3Stability of the object's composition
If endogenous IL-36Ra antagonist is maintained in the model, then the model maintains natural regulatory mechanisms, but the antagonist is 20-fold less potent and does not fully replicate DITRA pathology
Solution Approach 1:
The patent applies local quality by maintaining the endogenous IL-36Ra antagonist in its natural state while introducing humanized signaling components. This creates a localized discrepancy where the antagonist remains rodent-derived and less potent, while the signaling pathway becomes human-like and hyperactive, accurately reflecting the pathological state of DITRA patients.
Data Source
AI summary
This disclosure relates to genetically modified rodent animals and rodent models of human diseases. More specifically, this disclosure relates to genetically modified rodents whose genome comprises a humanized Il1rl2 gene (coding for the IL1rl2 subunit of the IL-36R protein) and human IL-36α, β and γ ligand genes. The genetically modified rodents disclosed herein display enhanced skin and intestinal inflammation as a preclinical model of psoriasis and IBD, respectively, and serve as a rodent model of human DITRA disease.