Pharmacological activation of LANCL2 is a novel immunometabolic mechanism for the treatment of psoriasis 2260624

Abstract

Abstract Introduction Psoriasis (PsO) is a chronic, inflammatory skin disease that afflicts 125 million people. Despite advancements in treatments, an unmet clinical need remains for safer and more effective therapeutics. LANCL2 is a novel immunoregulatory target for the treatment of a wide range of inflammatory and autoimmune diseases, including PsO. Methods We utilized the imiquimod (IMQ) mouse model to conduct comparative therapeutic studies of topical omilancor against current PsO standard of care (SOC) therapies such as anti-IL17, betamethasone and methotrexate. We also evaluated the therapeutic efficacy of next-generation oral LANCL2 drugs. Mice were challenged with IMQ in shaved dorsal skin for 7 d. Skin was evaluated for inflammatory lesions and immune cell subset infiltration. Proinflammatory cytokine production of PBMCs isolated from PsO patients was assessed in vitro upon pharmacological activation of LANCL2. Results LANCL2 therapeutics outperformed SOC and demonstrated the largest decrease in disease severity and typical signs of psoriatic lesions (epidermal hyperplasia and hyperkeratosis). Topical omilancor demonstrated similar efficacy reducing skin inflammation to the anti-IL-17 and betamethasone groups with the greatest decrease in skin inflammatory infiltrates and expression of proinflammatory mediators (Ccl20, S100A9, Il6). Next-generation LANCL2 drugs ameliorated disease severity and reduced the infiltration of proinflammatory subsets (neutrophils, IL-17+ cells). In translational studies using human PBMCs, activation of LANCL2 activation resulted in decreased production of proinflammatory cytokines (IL-8, IL1b, IL-6). Conclusion NIMML has characterized LANCL2 as a unique immunometabolic target for the treatment of PsO and demonstrated that LANCL2 therapeutics outperform SOC therapies to ameliorate disease, skin inflammatory lesions and to reduce systemic inflammation while managing comorbidities through oral, once-daily pharmacological LANCL2 activation. Funding Source N/A Topic Categories Therapeutic Approaches to Autoimmunity (THER)