Sulfated Polysaccharide Derivatives for the Treatment of Rosacea
Small Business Information
GLYCOMIRA, LLC, 675 ARAPEEN DR, STE 302, SALT LAKE CITY, UT, 84108
Name: NARAYANAM RAO
Phone: () -
Phone: () -
Name: TIMOTHY MILLER
Phone: (801) 550-9817
Phone: (801) 550-9817
AbstractDESCRIPTION (provided by applicant): Rosacea is a common disfiguring skin disease affecting 3% of the population over 30 years of age, or 14 million Americans. In men and women of Celtic origin, Rosacea causes central erythema of the face, with highly visible dilated blood vessels and pustules. Dry, itchy eyes are also common. In men, Rosacea can thicken the skin of the nose to create the classical W.C. Fields nose, or rhinophyma. The molecular etiology of Rosacea is the cutaneous over-production of cationic anti-microbial peptides cathelicidins and their processing serine proteases. Injection of Rosacea-like concentrations of the 37-amino acid C-terminal cleavage product of hCAP18, termed LL-37, into mouse skin reproduces the redness and polymorphonuclear leukocyte (PMN) infiltration characteristic of the disease. GlycoMira has synthesized several partially lipophilic, sulfated derivatives of a common polysaccharide that show anti-inflammatory activities at nanogram/ml concentrations, including inhibition of the cationic PMN protease human leukocyte elastase (HLE) and inhibition of the PMN adhesion receptor P-selectin. Most importantly, these sulfated and alkylated polysaccharides potently inhibit of the interaction of the receptor for advanced glycation end-products (RAGE) with its many ligands, including carboxy-methyl lysine albumin (CML-BSA), S100 calgranulins, and high mobility box group protein-1 (HMGB- 1). This Phase I project will test the hypothesis that topical application of these proprietary agents can be used as a novel therapy for Rosacea by the dual actions of charge neutralizing and inhibiting the cutaneous inflammatory activity of excess cationic cathelicidins in the skin of patients with this disease. In Aim 1, sixteen analogs will be synthesized and chemically characterized to explore structure-activity space by varying molecular size, sulfation and alkylation. In Aim 2 we will determine the biochemical activities of these compounds as inhibitors of P-selectin, HLE, and interaction of RAGE with four ligands. In Aim 3, we will evaluate the feasibility of using these compounds to prevent LL-37-induced IL-8 secretion by cultured human keratinocytes. Using the two most active compounds from in vitro experiments, in Aim 4 we will demonstrate the feasibility of using these selected active compounds to reduce the local erythema and dermal PMN infiltration in response to subcutaneous injection of LL-37 in mice. Following this feasibility study, GlycoMira will pursue a Phase II project to leverage the development of a topically-applied formulation of our lead drug, demonstrate its efficacy topically in blocking dermal toxicity from intra-dermal LL-37 injection, and complete the pre-clinical toxicology studies to support filing an investigational new drug application. PUBLIC HEALTH RELEVANCE: Rosacea is a common disfiguring skin disease affecting 3% of the U.S. population over 30 years of age, or 14 million Americans. Afflicting primarily Caucasian women of Celtic descent, Rosacea is characterized by erythema of the face with highly visible telangieactatic blood vessels, often with papules and pustules. Rosacea can also produce dry, itchy eyes and, in men, a bulbous thickened nose, or rhinophyma. There is no cure for the disease and its treatment is largely empiric and imperfect. We propose to develop anionic, partially lipophilic hyaluronic acid derivatives as the first mechanistically-based treatment for this chronic, disfiguring skin disorder.
* information listed above is at the time of submission.