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An α-MSH Analog in Erythropoietic Protoporphyria

      On 23 October 2014, the α-melanocyte-stimulating hormone (α-MSH) analog afamelanotide (Scenesse) attained approval as a first-in-class drug for patients with adult erythropoietic protoporphyria (EPP) who are extremely intolerant of UV and visible light. This successful drug-development program is the consequence of a determined effort to translate extensive basic research efforts.
      α-MSH was originally characterized as a pituitary-derived inducer of pigmentation (
      • Harris J.I.
      • Lerner A.B.
      Amino-acid sequence of the alpha-melanocyte-stimulating hormone.
      ). Notably, Lerner and co-workers were also the first to assess intradermally and intramuscularly injected α-MSH in patients with vitiligo. The clinical effect was limited to some perifollicular pigmentation, and subsequent attempts with adrenocorticotropin-like peptides were never encouraging enough to bring these melanocortin peptides into daily practice in dermatology (reviewed in
      • Böhm M.
      Proopiomelanocortin and related hormones in vitiligo.
      ). The reason for the limited clinical usefulness of α-MSH lies in its chemical structure—the tridecapeptide is too big for transcutaneous delivery; also, it rapidly degrades in the gastrointestinal tract when taken orally. In the presence of human plasma, the half-life of α-MSH is less than 30 minutes (
      ). One possible strategy to overcome this problem is chemical modification of the peptide without affecting the message and signal sequences required for the melanotropic effect of α-MSH. Among the plethora of MSH peptides tested by Hruby and co-workers, Nle-d-Phe7-α-MSH (NDP-α-MSH) emerged as one of the most potent and long-acting pigment-inducing synthetic melanocortin peptides (
      • Sawyer T.K.
      • Sanfilippo P.J.
      • Hruby V.J.
      • et al.
      4-Norleucine, 7-d-phenylalanine-alpha-melanocyte-stimulating hormone: a highly potent alpha-melanotropin with ultralong biological activity.
      ). The first clinical studies in the 1990s revealed that local subcutaneous injections of NDP-α-MSH increase skin pigmentation (
      • Levine N.
      • Sheftel S.N.
      • Eytan T.
      • et al.
      Induction of skin tanning by subcutaneous administration of a potent synthetic melanotropin.
      ;
      • Barnetson R.S.
      • Ooi T.K.
      • Zhuang L.
      • et al.
      Nle4-d-Phe7-alpha-melanocyte-stimulating hormone significantly increased pigmentation and decreased UV damage in fair-skinned Caucasian volunteers.
      ).
      Interestingly, anti-inflammatory and immunomodulatory effects were soon recognized during the functional characterization of α-MSH and found to reside within its C-terminal-tripeptide sequence (reviewed in
      • Catania A.
      • Lipton J.M.
      Alpha-melanocyte stimulating hormone in the modulation of host reactions.
      ). However, pharmaceutical exploitation of KPV has been unsuccessful until now. The field of melanocortin research rapidly expanded on cloning of the MC-Rs by Cone's group (
      • Mountjoy K.G.
      • Robbins L.S.
      • Mortrud M.T.
      • et al.
      The cloning of a family of genes that encode the melanocortin receptors.
      ). The five MC-Rs (MC-1-5R) belong to the superfamily of the G-protein-coupled receptors with seven transmembrane domains and differ with regard to their binding affinities for melanocortins. The human MC-1R binds α-MSH and adrenocorticotropin with similar affinity. Investigating various cell types and tissues with MC-R subtype–specific probes in combination with functional studies allowed identification of several novel targets of α-MSH within the skin and beyond.
      The main function of α-MSH within the skin becomes most apparent during UV-induced tanning. Sun exposure is a prototypical environmental stressor and increases expression of the proopiomelanocortin (POMC) as well as secretion of α-MSH in the skin (
      • Schiller M.
      • Brzoska T.
      • Böhm M.
      • et al.
      Solar-simulated UVR-induced upregulation of the melanocortin-1 receptor, pro-opiomelanocortin and α-melanocyte-stimulating hormone in human epidermis in vivo.
      ). The mechanism behind this phenomenon is complex and involves on one hand UV-induced activation of the tumor suppressor gene product p53 that subsequently binds to the POMC promoter in keratinocytes and turns on α-MSH expression (
      • Cui R.
      • Widlund H.R.
      • Feige E.
      • et al.
      Central role of p53 in the suntan response and pathologic hyperpigmentation.
      ). On the other hand, proinflammatory cytokines and mediators, some of them also players of the classical hypothalamic–pituitary–adrenal axis, orchestrate UV-mediated POMC expression and α-MSH secretion within the skin (reviewed in
      • Slominski A.
      • Wortsman J.
      • Luger T.
      • et al.
      Corticotropin releasing hormone and proopiomelanocortin involvement in the cutaneous response to stress.
      ). Melanocytes that express MC-1R most abundantly subsequently respond to UV-induced α-MSH expression with increased melanogenesis, proliferation dendrite formation, and melanin transfer to keratinocytes.
      The physiological role of MC-1R in the context of UV-induced pigmentation is highlighted by the finding of polymorphisms in the MC1R gene that are responsible for red hair and pale skin type. Carriers of loss-of-function alleles of MC1R have a higher risk for the development of melanoma and nonmelanoma skin cancer. Interestingly, this appears to be only partially dependent on the impact of MC-1R on skin pigmentation (
      • Beaumont K.A.
      • Liu Y.Y.
      • Sturm R.A.
      The melanocortin-1 receptor gene polymorphism and association with human skin cancer.
      ). Accordingly, α-MSH has been found to directly reduce the extent of UVB-induced genotoxic stress in melanocytes (for example, to reduce the amount of cyclopyrimidine dimers). In individuals with loss-of-function MC1R alleles, this cytoprotective effect of α-MSH is lost (reviewed in
      • Abdel-Malek Z.A.
      • Knittel J.
      • Kadekaro A.L.
      • et al.
      The melanocortin 1 receptor and the UV response of human melanocytes—a shift in paradigm.
      )
      Our picture of α-MSH in the skin, however, would be incomplete when leaving out the majority of other cell types responding to this molecule (reviewed in
      • Böhm M.
      • Luger T.A.
      • Tobin D.J.
      • et al.
      Melanocortin receptor ligands: new horizons for skin biology and clinical dermatology.
      ). In many of the above cell types, α-MSH was shown to suppress the activation of the transcription factor NF-κB α-MSH and thereby modulate production of proinflammatory cytokines and expression of adhesion molecules (reviewed in
      • Brzoska T.
      • Luger T.A.
      • Maaser C.
      • et al.
      Alpha-melanocyte-stimulating hormone and related tripeptides: biochemistry, antiinflammatory and protective effects in vitro and in vivo, and future perspectives for the treatment of immune-mediated inflammatory diseases.
      ). Among the most recently identified human target cells of α-MSH are basophilic granulocytes (
      • Böhm M.
      • Apel M.
      • Sugawara K.
      • et al.
      Modulation of basophil activity—a novel function of the neuropeptide α-melanocyte-stimulating hormone.
      ) and T cells (
      • Loser K.
      • Brzoska T.
      • Oji V.
      • Auriemma M.
      • et al.
      The neuropeptide alpha-melanocyte-stimulating hormone is critically involved in the development of cytotoxic CD8+ T cells in mice and humans.
      ;
      • Auriemma M.
      • Brzoska T.
      • Klenner L.
      • et al.
      α-MSH-stimulated tolerogenic dendritic cells induce functional regulatory T cells and ameliorate ongoing skin inflammation.
      ), both key players of the adaptive immune system that orchestrate allergic and inflammatory responses of the skin and mucosal membranes. Studies of these nonmelanocytic cells of the skin further extended our current view of the cytoprotective armamentarium of α-MSH. For example, α-MSH directly upregulates nuclear factor E2-related factor 2, a transcription factor crucially involved in cellular redox homeostasis and a regulator of antioxidative enzymes like heme oxygenase 1 (
      • Kokot A.
      • Metze D.
      • Mouchet N.
      • et al.
      α-Melanocyte-stimulating hormone counteracts the suppressive effect of UVB on Nrf2 and Nrf-dependent gene expression in human skin.
      ,
      • Kokot A.
      • Sindrilaru A.
      • Schiller M.
      • et al.
      α-Melanocyte-stimulating hormone suppresses bleomycin-induced collagen synthesis and reduces tissue fibrosis in a mouse model of scleroderma.
      ) (see Figure 1).
      Figure thumbnail gr1
      Figure 1Afamelanotide reduces tissue damage and pain resulting from sun exposure in EPP patients. UVA and UVB damage DNA directly and UVA also causes oxidative damage, releasing reactive oxygen species (ROS). Visible wavelengths, particularly the Soret band (400–410 nm), are absorbed by protoporphyrin IX (PPIX), generating more ROS. The resulting inflammation and nerve damage causes pain and swelling in the skin of EPP patients. Afamelanotide, injected subcutaneously in a sustained release formulation at 60-day intervals, is distributed systemically and binds MC-1 receptors. Increased epidermal melanin production and distribution after melanocyte MC-1R binding reduces the damaging UV and visible light penetration. Afamelanotide binding to MC-1R on all cell types in skin also enhances DNA repair, upregulates antioxidant enzymes, and reduces production of proinflammatory cytokines in both the dermis and the epidermis, minimizing the PPIX-mediated damage and resulting pain. EPP, erythropoietic protoporphyria.
      The pleiotropic cytoprotective properties of α-MSH provided the rationale for exploiting melanocortins as a new treatment in EPP. EPP is a rare autosomally inherited disease of porphyrin biosynthesis that is caused by mutations of ferrochelatase. As a consequence, the photosensitizer protoporphyrin IX accumulates in the skin, resulting in absolute sunlight intolerance. Upon sun exposure, EPP patients experience immediate, severe pain with subsequent erythema and edema. There is no effective therapy for this orphan disease, and often the only way that affected patients can prevent these symptoms is to strictly avoid daylight (
      • Minder E.I.
      • Schneider-Yin X.
      Afamelanotide (CUV1647) in dermal phototoxicity of erythropoietic protoporphyria.
      ). Using a sustained-release resorbable implant formulation that delivers 16 mg of NDP-α-MSH (afamelanotide), a pilot phase II trial was performed with five patients with EPP. The implant was administered subcutaneously, twice, 60 days apart. In all five patients, the time to provoke pain with an artificial xenon light source emitting UV light above 385 nm was significantly prolonged and associated with an increase in melanin density (
      • Harms J.
      • Lautenschlager S.
      • Minder C.E.
      • et al.
      An α-melanocyte–stimulating hormone analogue in erythropoietic protoporphyria.
      ). Additional phase II trials indicated beneficial effects of afamelanotide in patients with solar urticaria, acne, and vitiligo and confirmed a good safety profile as well (
      • Haylett A.K.
      • Nie Z.
      • Brownrigg M.
      • et al.
      Systemic photoprotection in solar urticaria with α-melanocyte-stimulating hormone analogue [Nle4-d-Phe7]-α-MSH.
      ;
      • Böhm M.
      • Ehrchen J.
      • Luger T.A.
      Beneficial effects of the melanocortin analogue Nle4-d-Phe7-α-MSH in acne vulgaris.
      ;
      • Lim H.W.
      • Grimes P.E.
      • Agbai O.
      • et al.
      Afamelanotide and narrowband UV-B phototherapy for the treatment of vitiligo: a randomized multicenter trial.
      ).
      Importantly, the initially observed promising effects of afamelanotide in EPP patients have been extended in several phase II and III trials (http://www.clinuvel.com/erythropoietic-protoporphyria). The results of these trials were significant with consistent effectiveness, a favorable risk–safety profile, and a high compliance rate for afamelanotide (
      • Minder E.I.
      • Schneider-Yin X.
      Afamelanotide (CUV1647) in dermal phototoxicity of erythropoietic protoporphyria.
      ). A recently published longitudinal observational study in 115 EPP patients treated with more than 1,023 afamelanotide implants from 2006 to June 2014 confirmed good clinical effectiveness and safety as well as durably improved quality-of-life scores under these long-term conditions (
      • Biolcati G.
      • Marchesini E.
      • Sorge F.
      • et al.
      Long-term observational study of afamelanotide in 115 patients with erythropoietic protoporphyria.
      ).
      The approval of afamelanotide by the European Medicines Agency in late 2014 can be regarded as a breakthrough for α-MSH in clinical medicine. This success is based on the year-long commitment of many scientists but also on the critical input of others (Clinuvel) at later stages. Indeed, EPP still cannot be cured by afamelanotide, and thus a long-term or even a lifelong management strategy for these patients is mandatory. Additional studies will be needed to further define the mode of action of afamelanotide in the skin of patients with EPP. For example, is the beneficial effect of afamelanotide in EPP patients due simply to increased epidermal pigmentation or is it related to reduced oxidative stress and nociception (Figure 1)? Is porphyrin metabolism perhaps directly targeted by α-MSH? It will be fascinating to answer these questions in the future and also to learn more about other possible indications for such α-MSH analogs.

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