Small Molecules for Lightening Skin

Using a genome-wide functional genomics approach designed to identify novel regulators of pigment production in human cells, researchers at UC Irvine determined that the enzyme aldehyde dehydrogenase (ALDH1A1) is novel regulator of pigment production. Small molecule ALDH inhibitors were found to inhibit melanin accumulation by inhibiting the expression of key genes that are exclusively expressed in pigment cells.   This mechanism is distinct from the mechanisms used by currently available pigment inhibitors. The most potent inhibitor found to date is the molecule cyanamide, a generic compound approved in Europe for alcohol aversion therapy. In vitro, cyanamide inhibits pigmentation in human skin cells. Cyanamide can inhibit melanin accumulation both histologically and quantitatively in skin equivalent models which closely mimic human skin.              The above figures demonstrate cyanamide can inhibit pigment accumulation in skin equivalents of darkly pigmented human skin (cyanamide, vehicle control, and kojic acid, a known skin lightener with side effects including skin irritation).UCI researchers developed and tested 5 formulations, identifying one formulation that performed markedly better than the others. The preferred formulation was tested on healthy human subjects and did not produce any significant irritation.Future Development PlansCompletion of stability testing is underway. We are currently looking for a commercial partner to further develop this product for skin lightening.

Patent Number: US20130101535A1
Application Number: US13598499A
Inventor: Ganesan, Anand | White, Michael A. | Farmer, Patrick J.
Priority Date: 29 Sep 2008
Priority Number: US20130101535A1
Application Date: 29 Aug 2012
Publication Date: 25 Apr 2013
IPC Current: A61K0031275 | A61K0031145
US Class: 424062
Assignee Applicant: Board of Regents the University of Texas Systemstin | The Regents of the University of California
Title: ALDEHYDE DEHYDROGENASE INHIBITORS AS NOVEL DEPIGMENTING AGENTS
Usefulness: ALDEHYDE DEHYDROGENASE INHIBITORS AS NOVEL DEPIGMENTING AGENTS
Summary: The method is useful for reducing skin pigmentation, where the skin pigmentation comprises hyperpigmentation due to sun exposure and inflammation, and hyperpigmentation associated with chemical exposure, and skin trauma and the subject has a disease or disorder including solar lentigines, Addison's disease, cushing's disease, acanthosis nigricans, melasma, linea nigra, peutz-jeghers syndrome, smoker's melanosis, celiac disease, cronkite-canada syndrome, and tinea fungal infection (all claimed). Tests details are described but no results given.
Novelty: Reducing skin pigmentation e.g. hyperpigmentation due to sun exposure and inflammation, comprises topically administering an inhibitor of aldehyde dehydrogenase

Biomedical

Medical Cosmetics

8802733

Features/Benefits

• Our cyanamide formulation is effective in lightening human skin equivalents, is not sensitizing to mouse tails, and is non-irritating in a human RIPT study with human volunteers (>50 human subjects).
• Aldh1 (the target of cyanamide) depletion was shown to inhibit melanogenesis in both lightly pigmented and darkly pigmented melanocytes
• Cyanamide has been used in humans systemically for the treatment of alcoholism (oral formulation), therefore safety profile in humans is known.
• Known mechanism of action.
• Cyanamide inhibits melanin accumulation via a novel mechanism – it blocks the expression of melanogenic genes that are expressed in pigment cells.

Publications

• “Genome-Wide siRNA-Based Functional Genomics of Pigmentation Identifies Novel Genes and Pathways That Impact Melanogenesis in Human Cells.” PLOS December 2008, Vol 4 (12): e1000298
• “9-cis Retinoic Acid is the ALDH1A1 Substrate that Stimulates Melanogenesis in Human Skin.”  http://onlinelibrary.wiley.com/doi/10.1111/exd.12099/abstract

Tech ID/UC Case

18741/2007-640-0

Related Cases

2007-640-0

USA

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