Oral Presentation ANZBMS-MEPSA-ANZORS 2022

Harnessing peptide-based therapy to control inflammatory disease (#33)

Scott N Byrne 1 2 , Anneliese S Ashhurst 1 2 3 , Joshua WC Maxwell 3 4 , Jack Rawlings 1 2 , Skye Stockdale 1 , Anica Avila 1 2 , David M McDonald 1 3 , Akane Tanaka 5 , Kirstie M Bertram 1 2 , Cameron C Hanna 3 , Rahael R Ireland 1 2 , Angela L Ferguson 1 , Sheila Donnelly 5 , Andrew N Harman 1 2 , Richard J Payne 3 4
  1. The University of Sydney, School of Medical Sciences, Faculty of Medicine and Health, NSW, Australia.
  2. The Westmead Institute for Medical Research, Centre for Immunology and Allergy Research , NSW, Australia.
  3. School of Chemistry, Faculty of Science, The University of Sydney, NSW, Australia.
  4. Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Sydney, Sydney NSW 2006, Australia
  5. School of Life Sciences, Faculty of Science, The University of Technology Sydney, NSW, Australia.

Inflammatory skin diseases such as psoriasis, which affects up to 4% of the Western population, can be highly debilitating. Current therapies are not consistently efficacious, can be costly and risk substantial adverse effects. New therapies that provide cost-effective and targeted suppression of inflammation are needed. We have uncovered a novel role for a human peptide in modulating and suppressing inflammation. A version of this peptide (called RP23) was produced by chemical synthesis with modifications to enhance ease of production. Culture of primary macrophages with RP23 led to reduced IL-12/23(p40) and IL-6 release after TLR-stimulation. When injected intra-dermally into human skin explants, RP23 reduced activation of dermal dendritic cells. In a mouse model of contact dermatitis, an injection of RP23 prior to sensitisation significantly suppressed elicitation of inflammation. Further, in a murine model of imiquimod-induced psoriasis, RP23 reduced erythema, skin thickness and scaling, reduced T-cells in psoriatic skin and increased the proportion of FoxP3+ CD4+ T-cells in local lymph nodes. Upon application in a topical formulation, RP23 penetrated the stratum corneum and colocalised with cells in the epidermis and dermis of human skin explants. Importantly, topical RP23 significantly suppressed psoriatic disease in mice when given either prophylactically or therapeutically, and synergistically enhanced therapeutic efficacy of topical steroid use. Reductions in disease were isolated to the local area in which RP23 was delivered, unlike topical glucocorticoid or injected monoclonal antibody therapy, which caused systemic immune suppression. RP23 therefore offers potential for development as a novel, locally acting peptide-based therapy for patients seeking improved management of inflammatory skin diseases.