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Abstract
Grant Number: 1R41CA114923-01A2 Project Title: DNA Repair Enzymes for the Prevention of Skin Cancer
PI Information: Name Title MCCULLOUGH, AMANDA K. mcculloa@ohsu.edu Abstract: DESCRIPTION (provided by applicant): Exposure of human skin to ultraviolet light (UV) triggers a progression of events that is initiated by DNA damage and immune suppression and can ultimately result in mutagenesis, cell proliferation, actinic keratoses, and skin cancers. The occurrence of these diseases is rapidly increasing, affecting over 1 million people in the United States annually. The carcinogenic effects of UV light are directly mediated by dipyrimidine DNA photoproducts. Human cells have only one mechanism to repair these DNA lesions, while lower organisms possess multiple pathways to repair the deleterious consequences of UV- induced DNA damage. In order to implement proactive strategies to treat and prevent several human diseases, including skin cancer, that can be directly attributed to inefficient repair of UV-induced DNA lesions, the founders of Restoration Genetics, Inc. have discovered, characterized and patented multiple DNA repair enzymes that possess catalytic activities that can initiate the BER pathway in human cells. These highly stable, patented enzymes have been engineered to specifically localize to the nucleus, thus significantly increasing the repair efficiency. Pilot studies have demonstrated the feasibility of incorporating these enzymes in an active form in liposomes that, upon topical application to skin, enhance DNA repair of UV light-induced DNA damage. In order to maximize efficacy of these enzymes to accelerate DNA repair in reconstituted human skin, the following aims are proposed: 1) Purify and encapsulate the nuclear forms of the patented enzymes in a variety of liposomal targeting vehicles that are used for topical skin delivery; 2) Test the efficacy of the enzymes using fully-differentiated human skin culture in multiple short-term assays. The commercial market potential for this technology is diverse and will include pharmaceutical applications for the prevention of skin cancers. The ultimate goal of these investigations is to reduce UV-induced skin cancers and immunosuppression through topical delivery of high specific activity DNA repair enzymes that localize to critical subcellular organelles. Acute and chronic exposure to sunlight is a primary risk factor for skin cancer. Human cells possess only one mechanism for the repair of UV-induced DNA damage. Our laboratories have patented new enzymes that activate a second DNA repair pathway. Thus, our technology will augment and dramatically improve human DNA repair capacity for removal of sunlight-induced damage. The anticipated societal benefits are to significantly reduce the number and average age of onset of new skin cancers.
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Institution: RESTORATION GENETICS, INC. 3037 NW 123RD PL PORTLAND, OR 972293993 Fiscal Year: 2007 Department: Project Start: 01-AUG-2007 Project End: 31-JUL-2008 ICD: NATIONAL CANCER INSTITUTE IRG: ZRG1