DNA Repair Enzymes for the Prevention of Skin Cancer

描述（由申请人提供）：人体皮肤暴露于紫外线（UV）会引发一系列由DNA损伤和免疫抑制引发的事件，并最终导致突变、细胞增殖、光化性角化病和皮肤癌。这些疾病的发病率正在迅速增加，每年影响美国100多万人。紫外线的致癌作用是由双嘧啶DNA光产物直接介导的。人类细胞只有一种机制来修复这些DNA损伤，而低等生物有多种途径来修复紫外线诱导的DNA损伤的有害后果。为了实施积极主动的策略来治疗和预防几种人类疾病，包括皮肤癌，这些疾病可直接归因于紫外线诱导的DNA损伤修复效率低下，Restoration Genetics, Inc.的创始人发现、鉴定并获得了多种DNA修复酶的专利，这些酶具有催化活性，可以启动人体细胞中的BER途径。这些高度稳定的专利酶被设计成专门定位于细胞核，从而显著提高修复效率。初步研究已经证明了将这些酶以活性形式加入脂质体的可行性，在局部应用于皮肤后，可以增强紫外线诱导的DNA损伤的DNA修复。为了最大限度地提高这些酶在重建人类皮肤中加速DNA修复的功效，提出了以下目标：1)纯化并将专利酶的核形式包封在各种用于局部皮肤递送的脂质体靶向载体中；2)用完全分化的人皮肤培养物在多个短期试验中测试酶的功效。这项技术的商业市场潜力是多种多样的，将包括预防皮肤癌的制药应用。这些研究的最终目标是通过局部递送定位于关键亚细胞细胞器的高比活性DNA修复酶来减少紫外线诱导的皮肤癌和免疫抑制。急性和慢性暴露在阳光下是皮肤癌的主要危险因素。人类细胞只有一种机制来修复紫外线诱导的DNA损伤。我们的实验室已经获得了激活第二种DNA修复途径的新酶的专利。因此，我们的技术将增强和显著提高人类DNA修复能力，以消除阳光引起的损伤。预期的社会效益是显著减少新发皮肤癌的数量和平均发病年龄。

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.