New York University

Harold Brem

Marjana Tomic-Canic

Herbert H Samuels

Marjana Tomic

It has been discovered that vascular endothelial growth factor ('VEGF') promotes migration of activated (but not differentiating) keratinocytes to skin. This growth factor specifically increases migration of keratinocytes of the 'wounded skin' phenotype but does not have significant effects upon differentiated keratinocytes. It also increases collagen deposition and reduces wrinkles, enhances skin quality, and increases skin thickness to normal levels in individuals where skin has thinned due to age or disorder such as diabetes. It is particularly well suited for use as cosmeceuticals when applied in purified form and in known amounts. The data presented in the examples demonstrate efficacy and specificity of VEGF in enhancing migration of normal human keratinocytes as well as formation of new granulation tissue including collagen formation. VEGF induces keratinocyte and fibroblast migration, formation of new tissue, and not only induces deposition of collagen but improves alignment of the collagen fibers. Accordingly, this growth factor is highly suitable for use as a cosmeceutical, especially for skin resurfacing and reduction in wrinkles.

Methods of increasing collagen formation and cellular migration in intact skin

Compositions for antagonizing phosphorylation and subsequent degradation of glycogen synthase kinase 3 beta (GSK3&#x3b2;) in epidermal cells are disclosed. GSK3&#x3b2; phosphorylation antagonists include molecules that function to inhibit or reduce the binding activity or enzymatic activity of an upstream signaling molecule leading to GSK3&#x3b2; phosphorylation, or by downregulating the expression of one or more upstream signaling molecules involved in regulating GSK3&#x3b2; phosphorylation. Methods of using the GSK3&#x3b2; phosphorylation antagonists to inhibit or reduce the phosphorylation and degradation of GSK3&#x3b2; in epidermal cells are provided. The methods are useful to promote epithelialization and closure of wounds, such as chronic non-healing wounds.

Methods for promoting epithelialization and healing of chronic wounds

The present invention relates to methods and compositions that control, i.e., antagonize/inhibit or agonize/stimulate, de novo glucocorticoid production in the skin. Such methods and compositions can be used for the prevention and/or treatment of a variety of skin conditions, including inflammation, acute wounds, chronic non-healing wounds, keloid, fibrotic or hypertrophic scars, and epithelial-derived cancer.

De novo synthesis of glucocorticoids in the epidermis and its uses and applications

It has been discovered that granulocyte macrophage colony stimulating factor ('GM-CSF') promotes migration of activated (but not differentiating) keratinocytes to wound sites. It was also discovered that GM-CSF increases the quantity and improves the quality of collagen. This growth factor specifically increases migration of keratinocytes of the 'wound' phenotype but does not have significant effects upon differentiated keratinocytes. Examples demonstrate reversal of skin impairment in multiple animal models of diabetic skin imparment when provided in an effective amount over an effective time period. The examples also demonstrate the efficacy of the formulations in cosmetic applications. A preferred formulation is a sustained release formulation that delivers sufficient growth factor to the skin and the underlying tissue thereof to increase the rate of keratinocyte migration, as well as collagen deposition and fibroblast proliferation, in the skin to promote rejuvenation of skin injuries resistant to repair due to underlying disease, such as diabetes, or aging.

GM-CSF cosmeceutical compositions and methods of use thereof

A method and means have been developed to deliver a therapeutic dose or dosages of the angiogenic molecule, Vascular Endothelial Growth Factor (VEGF) that results in a statically significant decrease in the time to achieve 100% wound closure and accelerates the rate of healing in experimental diabetic ulcers. Toxicity is evaluated by measuring any local inflammatory response at the wound site, the systemic absorption of VEGF, and the effect on distant organs that may be particularly susceptible to VEGF therapy (e.g., retinopathy and hepatitis) The angiogenic response is quantified by measuring the change in collagen deposition, epithelialization, and the closure rates of diabetic ulcers after therapeutic dosing with ADV-VEGF. Sustained administration of VEGF, stimulates and accelerates the healing process as evidenced by a reduced time to complete healing (defined by 100% epithelialization and no drainage) in experimental diabetic ulcers, with minimal to no toxicity. Important features of the method and reagents for use therein are that the VEGF is released into the ulcer in a sufficient quantity over a period of time for at least two to six weeks, or to closure of the wound.

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Bronx, NY, United States of America

Harold Brem