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Treatment for Vitiligo

 

OHSU # 1020

Summary:

Piperine, Vitiligo and Melanoma

Technology 1020 Amala Soumyanath, PhD

Technology Overview

Piperine (PIP) is a natural compound that shows potential as a topical treatment for vitiligo and for melanoma. PIP has the unique ability to stimulate normal melanocyte replication, but also inhibit the growth of malignant melanocytes in vitro and in vivo. PIP has been successfully formulated and applied in animal models as a topical therapeutic candidate. OHSU owns a patent portfolio relating to the composition of matter, and methods of use of PIP and PIP derivatives for vitiligo and for melanoma. OHSU is looking for commercial licensees to develop and bring a PIP product to market.

Background

Vitiligo is a chronic depigmentary skin disease, characterized by the absence of melanocytes (pigment cells) in regions of the skin1. It has worldwide prevalence of 1.1%, but only poor treatment options exist 2. According to the Americal Academy of Dermatology, vitiligo can be life altering causing patients to become self-conscious about the appearance of their skin, lowering their self-esteem, inhibiting frequency and quality of social interaction, and potentially leading to serious depression. There is a significant unmet medical need for an effective topical treatment for vitiligo.

PIP offers a potentially innovative approach to treating vitiligo, by stimulating melanocyte proliferation from hair follicles and perilesional skin. Since PIP does not stimulate melanin (pigment) synthesis per se, it would best be used with narrow band UVB (NB-UVB; 311nm), a current therapy for vitiligo. Potential advantages over NB-UVB alone are accelerated repigmentation of lesions, reduction in radiation exposure, and more uniform skin color. There may also be potential for PIP in products for use against melanoma, as PIP shows therapeutic effects in melanoma models.

Market Potential

Vitiligo: Global Data estimated the global vitiligo therapeutics marketplace to be worth of $1.4 billion in 2011. It is expected to grow to $2.7 billion by 2019 at a Compound Annual Growth Rate (CAGR) of 8.8%.

Melanoma: Melanoma is a major cause of mortality worldwide, with a prevelance of about 0.07%, accounting for almost 8,000 deaths a year in the US alone. Therapeutic treatments for melanoma are currently a $3 billion market but aside of protection from UV exposure; there are currently no recommended means of limiting melanoma incidence.

PIP for Vitiligo - Supporting Data:

Our published, preclinical data 3-8 has demonstrated PIP’s potential as a treatment for vitiligo. PIP and several derivatives stimulate mouse melanocyte proliferation in vitro 4,6,8. PIP shows selective in vitro stimulation of melanocytes, and a remarkable inhibitory effect on B16 F10 mouse melanoma cells 9. PIP increases visible pigmentation in a sparsely pigmented mouse model 3, 5. Active melanocytes increased from 3 per mm2 in untreated animals to 250 per mm2 after 13 weeks topical treatment with PIP3, 5. Concomitant UV treatment enhances these effects, but significantly, pigmentation is more rapid and greater with PIP plus UV, than with UV alone. Pre-stimulation of melanocyte proliferation by PIP prior to UV treatment led to even skin re-pigmentation, unlike the freckled appearance observed with UV alone. No adverse effects, other than mild skin inflammation and irritation, were seen when compounds were administered over a 13-week period, with or without UV. Furthermore PIP did not form DNA adducts in vitro either before or after UV 5 suggesting an absence of genotoxicity. PIP also stimulates the replication of human melanocytic cell lines and human melanocytes in reconstructed human epidermis in vitro (manuscript in preparation).

PIP for Melanoma - Supporting Data:

We expect that PIP will inhibit melanoma development, based on the following strong evidence from our own studies and the literature:

a) PIP shows a potent inhibitory effect on melanoma cells in monoculture, and reduces the growth and metastases of melanoma implanted in mice 9, 10, 11.

b) PIP inhibits the growth of human melanoma cells in reconstructed human full skin (manuscript in preparation).

c) In our preliminary (unpublished) gene expression studies, PIP showed several effects on mouse melanocyte (melan-a cells) suggestive of a benign melanocyte stimulatory action and potential chemopreventive effect against melanoma.

d) PIP shows inhibitory effects on carcinogen-induced non-melanoma skin cancer (NMSC) development in mice 12.

Relevant Publications

1. Ortonne JP, Mosher DB, Fitzpatrick TB. Vitiligo and other hypomelanosis of hair and skin. In: New York/London: Plenum; 1983:129-310.

2. Whitton ME, Pinart M, Batchelor J, Lushey C, Leonardi-Bee J, Gonzalez U. Interventions for vitiligo. Cochrane Database Syst Rev. 2010(1):003263.

3. Faas L, Venkatasamy R, Hider RC, Young AR, Soumyanath A. In vivo evaluation of piperine and synthetic analogs as potential treatments for vitiligo using a sparsely pigmented mouse model. British Journal of Dermatology. 2008;158:941-950.

4. Lin Z, Liao Y, Venkatasamy R, Hider RC, Soumyanath A. Amides from piper nigrum L. with dissimilar effects on melanocyte proliferation in-vitro. J Pharm Pharmacol. 2007;59(4):529-536.

5. Soumyanath A, Venkatasamy R, Joshi M, et al. UV irradiation affects melanocyte stimulatory activity and protein binding of piperine. Photochem Photobiol. 2006;82(6):1541-1548.

6. Lin Z, Hoult JR, Bennett DC, Raman A. Stimulation of mouse melanocyte proliferation by piper nigrum fruit extract and its main alkaloid, piperine. Planta Med. 1999;65(7):600-603.

7. Lin ZX, Donatien P, Raman A, Bennett DC. A naturally occurring growth promoter for human melanoblasts in culture. Journal of Pharmacy & Pharmacology. 1998;50 (supplement):218.

8. Venkatasamy R, Faas L, Young AR, Raman A, Hider RC. Effects of piperine analogues on stimulation of melanocyte proliferation and melanocyte differentiation. Bioorg Med Chem. 2004;12(8):1905-1920.

9. Lin ZX. Screening and bioassay guided fractionation of selected plants used in the treatment of vitiligo. [Doctor of Philosophy]. London University; 1999.

10. Pradeep CR, Kuttan G. Piperine is a potent inhibitor of nuclear factor-kappaB (NF-kappaB), c-fos, CREB, ATF-2 and proinflammatory cytokine gene expression in B16F-10 melanoma cells. Int Immunopharmacol. 2004;4(14):1795-1803.

11. Pradeep CR, Kuttan G. Effect of piperine on the inhibition of lung metastasis induced B16F-10 melanoma cells in mice. Clin Exp Metastasis. 2002;19(8):703-708.

12. Vellaichamy L, Balakrishnan S, Panjamurthy K, Manoharan S, Alias LM. Chemopreventive potential of piperine in 7,12-dimethylbenz[a]anthracene-induced skin carcinogenesis in swiss albino mice. Environ Toxicol Pharmacol. 2009;28(1):11-18. doi: 10.1016/j.etap.2009.01.008.

Inventors:

Patents:

IssuedUnited Kingdom1094813
IssuedMexico219346
IssuedAustralia
IssuedCanada2,434,775
Notice of allowanceEuropean Patent Convention
IssuedItaly1094813
IssuedIreland1094813
IssuedFrance1094813
IssuedUnited States6,346,539
IssuedUnited States6,680,391
IssuedUnited States7,122,561
IssuedSouth Africa2000/4260
IssuedUnited States7,361,685 B2
IssuedGermany69911210.9
IssuedHong KongHK1033264
IssuedEuropean Patent Convention1094813
IssuedChinaZL 99810839.1
IssuedCanada2,337,205
IssuedMexico294413
IssuedSouth Africa2003/5432
IssuedCanada2,735,844

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Travis Cook
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