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Project J3-70144
Development of new peptide therapies for the treatment of autoimmune and allergic diseases
Research project ARIS
Code: J3-70144
Period 1.3.2026 - 28.2.2029
Head: Assoc Prof Peter Korošec, BSc (Biol), PhD
ARIS classification : Medicine/Microbiology and Immunology
Organisations: University Clinic of Respiratory and Allergic Diseases Golnik; University Medical Centre Ljubljana; University of Ljubljana, Faculty of Pharmacy
Description of the project
Autoimmune diseases and food allergies range from 4 to 5% and up to 10% of the general population, and it is expected that both increase globally. The care of patients with autoimmune diseases or food allergies is often challenging, and despite recent advances in immunosuppressive treatments and immunotherapy, the burden of those diseases remains high. Currently, there is no effective cure for some severe autoimmune diseases, like systemic sclerosis, and for peanut anaphylaxis. Further, there is no therapeutic approach to development and progress of IgG autoantibodies in systemic sclerosis, and peanut IgE sensitization in peanut anaphylaxis highlights the need to develop effective prevention strategies.
Of all autoimmune diseases, systemic sclerosis has the highest mortality and clinical complications due to the lack of disease-modifying therapies targeting the fibrotic process. IgG autoantibodies to topoisomerase 1 are specific for systemic sclerosis and predictive for more severe disease and development of fibrosis and heart involvement. Importantly, autoantibodies to topoisomerase 1 occur several years before the overt disease, and this period may be the ideal treatment niche for blocking those antibodies and preventing the development of systemic sclerosis. Currently, there is no fully approved drug for treating peanut allergy and anaphylaxis, highlighting the critical need to develop new therapies for food allergies. In addition to Ara h 2, Ara h 1 and 3 are the major peanut allergens and important predictors of clinical reactivity. IgE crosslinking to peanut allergens induces rapid degranulation and release of mediators from mast cells and drives the clinical manifestations of an allergic reaction.
Clinical and experimental analyses indicate a pathognomonic role for IgG autoantibodies to topoisomerase 1 in systemic sclerosis and Ara h 1 and 3 in peanut-induced anaphylaxis. Consequently, the binding of IgG autoantibodies to topoisomerase 1 through paratope epitopes is a significant initial step in the cascade leading to systemic sclerosis, and Ara h 1 and 3 IgE crosslinking through paratope epitopes is also a significant initial step leading to peanut anaphylaxis. Therefore, we hypothesize that A: in systemic sclerosis, topoisomerase 1 epitope peptides bind paratopes of IgG autoantibodies and inhibit the initial step in the development of systemic sclerosis, and B: in peanut anaphylaxis Ara h 3 epitope peptides can bind paratopes of IgE antibodies and, thus, stopping an allergic reaction.
In this project, we want A: to discover and characterize unique topoisomerase 1 IgG epitope peptides and asses if these peptides can block the binding of autoantibodies to topoisomerase 1 and thus possibly suppress the development of systemic sclerosis; B: to discover and characterize unique Ara h 1 and 3 IgE epitope peptides and asses if these peptides can block the binding of IgE antibodies to Ara h 1 and 3 and thus stop the allergic reaction to peanuts. Validation: For validation, we will select another severe autoimmune disease, thrombocytopenic purpura, caused by ADAMTS13 autoantibodies.
Identification of linear and conformational epitopes will be performed with a state-of-the-art epitope and peptide microarray based methods and advanced computational analysis with the collaboration of three major Slovenian centers; Golnik Clinic (leading in allergy), Rheumatology Clinic (leading in autoimmune) and Faculty of Pharmacy (leading in optimization for drug-like properties). Patient cohorts will be recruited from Slovenia, Belgium, the UK, and the US. Importantly, we want to develop a personalized strategy for epitope–paratope blocking, evaluate individual epitope IgG or IgE binding profiles and select epitope peptides with the most potent blocking potential for each profile.