Oral Presentation 14th Australian Peptide Conference 2022

Self-derived immunomodulatory peptide RP23 as a novel therapeutic for inflammatory skin diseases (#57)

Anneliese Ashhurst 1 2 , JWC Maxwell 1 3 , J Rawlings 2 , A Avila 2 4 , DM McDonald 2 , A Tanaka 5 , KM Bertram 4 , CC Hanna 1 , RA Ireland 2 , S Donnelly 5 , A Harman 4 , SN Byrne 2 4 , RJ Payne 1 3
  1. School of Chemistry, University of Sydney, Sydney, NSW, Australia
  2. School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
  3. Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, University of Sydney, Sydney, New South Wales, Australia
  4. The Westmead Institute for Medical Research, Sydney, NSW, Australia
  5. School of Life Sciences, Faculty of Science, The University of Technology Sydney, Ultimo, NSW, Australia

Inflammatory skin diseases such as psoriasis, which affect up to 4% of the Western population, can be highly debilitating. Current therapies are not consistently efficacious for all patients, can be costly and carry a risk of substantial adverse effects. New therapies that provide cost-effective and targeted suppression of inappropriate 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, and also allow tagging to track the peptide in immunological studies. Culture of primary human or murine macrophages with RP23 led to reduced IL-12/23(p40), IL-6 and MCP-1 release after TLR-stimulation. When injected intra-dermally into human skin explants, RP23 reduced spontaneous activation of dermal dendritic cells. In a mouse model of contact dermatitis, a single 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 skin draining lymph nodes. Upon application in a topical formulation, RP23 penetrated the stratum corneum and colocalised with cells in the epidermis and dermis of murine and human skin explants. Importantly, topical RP23 significantly suppressed psoriatic disease in mice when given either prophylactically or therapeutically, and synergistically enhanced therapeutic efficacy of short-term topical steroid use. Topical RP23 also reduced severity of disease in a murine model of atopic dermatitis (oxazolone-induced). 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.