PD05 The effects of afamelanotide on ultraviolet radiation-induced acute inflammatory and DNA repair responses in healthy human skin
Authors: Peake Michael , Rutter Kirsty , Griffin Liezel , Nucci Jessica , Drysdale Eleanor , Bilbao Pilar , Juarranz Angeles , Farrar Mark , Rhodes Lesley E 
Published: June 2024

Abstract
Afamelanotide, a potent analogue of α-melanocyte-stimulating hormone, is known to stimulate melanogenesis by binding to the melanocortin 1 receptor. Additionally, in experimental models it has anti-inflammatory and antioxidative effects. Consequently, afamelanotide is employed and under development as a therapeutic agent for patients with photodermatoses, who can experience debilitating effects from exposure to sunlight’s ultraviolet radiation (UVR) and visible light. However, limited knowledge exists regarding the scope of the effects of afamelanotide in humans in vivo. This study evaluated the short-term impact of afamelanotide on UVR-induced acute inflammatory and DNA damage repair skin responses in healthy volunteers. Skin biopsies from seven healthy volunteers (skin type II–III, age range 27–43 years) were taken firstly prior to afamelanotide treatment, and procedures were then repeated 6 days following administration of a single 16-mg subcutaneous implant of afamelanotide. Volunteers received 2 × minimal erythema doses of UVR (broadband UVB, Philips TL12 lamp; Philips, Amsterdam, the Netherlands) to buttock skin. Biopsies were collected 24 h post-UVR exposure and from unirradiated skin, before and after afamelanotide administration. Samples underwent gene expression analysis using bulk RNA-Seq and Ingenuity Pathway Analysis. Transcriptomic analysis demonstrated that without afamelanotide, UVR irradiation resulted in 625 significantly differentially expressed genes (DEGs) compared with nonirradiated skin (&gt; 1 log2 fold change, q &lt; 0.05). In contrast, with afamelanotide, the DEGs between irradiated and nonirradiated skin reduced to 183, a factor of 3.4 less DEGs. These included genes associated with inflammatory and immune responses, including tumour necrosis factor (TNF) receptors and interleukins, and with DNA repair. Top predicted upstream regulators (with the highest z-score) in UVR-irradiated vs. nonirradiated skin were the same regardless of afamelanotide treatment. These included proinflammatory mediators such as TNF, interleukin-1 signalling, interferon-γ, and Toll-like receptor 3. However, the number of DEGs associated in the predicted activation of such upstream regulators and overall z-scores were reduced in skin following afamelanotide administration. Additionally, in untreated skin, UVR-induced proinflammatory pathways were enriched, but conversely this was not observed in skin following afamelanotide intervention. Oxidative stress and DNA damage repair pathways also appeared reduced after afamelanotide intervention, including oxidative-stress-induced senescence, DNA methylation and the DNA double strand break response. Transcriptomic analysis also demonstrated that, through comparison of skin under the same irradiation conditions, intervention with afamelanotide significantly upregulated premelanosome protein (PMEL gene), which plays a role in the synthesis of melanosomes. In conclusion, in addition to promoting melanogenesis, in this study afamelanotide reduced the magnitude of UVR-induced proinflammatory and DNA damage repair and oxidative stress responses in human skin, indicating its potential broad, innovative scope in treatment of UVR-induced skin disorders. This research was sponsored by CLINUVEL (UK) Ltd.