Melanotropic Peptides: more than Just 'Barbie Drugs' and 'Sun-tan Jabs'?

E.A. Langan; Z. Nie; L.E. Rhodes

Disclosures

The British Journal of Dermatology. 2010;163(3):451-455. 

In This Article

Potential Applications in Dermatology

Recent and ongoing phase II and III clinical trials are exploring the photoprotective potential of a controlled release subcutaneous implant formulation of [Nle4-D-Phe7]-α-MSH, afamelanotide (SCENESSE®, Clinuvel Pharmaceuticals Ltd) for clinical applications in dermatology. These currently focus on applications in the prevention of actinic keratoses and squamous cell carcinoma in organ transplant recipients, and as a strategy for protection in patients with photosensitivity disorders.[22]

Melanin acts as a broad chromophore in the skin, absorbing UVB, UVA and visible light (Fig. 2). Thus, with its ability to induce prolonged skin melanin production [Nle4-D-Phe7]-α-MSH is a potential approach for the prophylaxis of skin diseases triggered and/or exacerbated by sunlight, including visible light, against which sunscreens, even when applied optimally, provide minimal protection, and while avoiding the UVR-associated DNA damage that may occur with 'hardening' phototherapy. The photosensitivity disorders, including erythropoietic protoporphyria (EPP), solar urticaria (SU) and polymorphic light eruption (PLE), lack fully effective treatments and result in significant morbidity;[23–25] increased melanization may increase individual thresholds to symptom/rash provocation.

Figure 2.

Illustration of the broad absorption by melanin across ultraviolet (UV) B, UVA and visible radiation wavebands.

EPP is a rare genetic disorder where accumulation of the photosensitizer protoporphyrin IX causes sensitivity to visible light. Presently, partial relief may be gained from beta-carotene and phototherapy, and the condition can impact considerably upon patients' quality of life.[23,25] Harms et al.[26] recently hypothesized that [Nle4-D-Phe7]-α-MSH would induce pigmentation in the skin of patients with EPP and that this would attenuate photoaggravation and consequently reduce skin pain experienced. In an open-label study of five subjects with EPP over 4 months, patients received a subcutaneous implant of afamelanotide at day 7 and at week 8. Skin melanin density increased when compared with baseline, accompanied by an increase in tolerance to photoprovocation, assessed by time taken to reach intolerable pain on light exposure. This is a subjective end-point, and randomized controlled studies are ongoing, further to explore the potential for treatment of EPP with afamelanotide. The mechanism of action of afamelanotide in EPP could potentially involve more than melanization alone, and thus the measure of protection could vary depending on photosensitivity disorder. While increased melanization will reduce penetration of optical radiation and may thus increase symptom threshold, the parent α-MSH molecule is reported experimentally to possess antioxidant, anti-inflammatory and immunomodulatory properties, as discussed earlier.[14]

Ongoing trials are evaluating afamelanotide in hospital-based patients with SU and PLE. SU is a rare immune-mediated photosensitivity disorder triggered by UVR and/or visible light, with a large impact on quality of life.[27] First-line treatment is antihistamines, avoidance of exposure and photoprotection. Other treatment strategies are 'skin hardening' through repeated exposure to UVR, beneficial in some, and plasmapheresis, effective in some patients but often a difficult modality to procure. PLE, on the other hand, is a common inflammatory photosensitivity disorder, with evidence of underlying immune mediation, the moderate to severe forms of which are associated with significant morbidity.28 Exposed sites are less sensitive to rash provocation; this may be due to skin 'hardening', whereby these areas of skin are more pigmented and thickened and hence more tolerant of UVR. The pigmentation may be replicated, without the UVR exposure that triggers the condition, using [Nle4-D-Phe7]-α-MSH.

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