DNA Repair Enzymes for the Prevention of Skin Cancer

用于预防皮肤癌的 DNA 修复酶

• 批准号: 8198809
• 负责人: AMANDA K MCCULLOUGH
• 金额: $ 65.86万
• 依托单位: RESTORATION GENETICS, INC.
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8198809
• 关键词: Ablation; Actinic keratosis; Acute; Address; Advocate; Affect; Age of Onset; Animals; Apoptosis; Apoptotic; Awareness; Basal Cell; Base Excision Repairs; Biochemical; Biological; Biological Assay; Biological Process; Biological Testing; Burn injury; Cancerous; Cells; Chemicals; Chlorella; Chronic; Clinical; Clinical Trials; Collaborations; Combined Modality Therapy; Complement; Contracts; Cutaneous Melanoma; DNA Damage; DNA Repair; DNA Repair Enzymes; DNA Repair Pathway; DNA glycosylase; DNA lesion; Data; Development; Diagnosis; Diagnostic; Disease; Disease Management; Drug Kinetics; Encapsulated; Enzymes; Escherichia coli; Excision; Excretory function; Exposure to; Family suidae; Fermentation; Frequencies; Funding; Future; General Population; Genetic; Half-Life; Health Care Costs; Health Sciences; Healthcare; Human; Immunosuppression; In Vitro; Inbred HRS Mice; Individual; Investigation; Kinetics; Laboratories; Legal patent; Lesion; Life; Light; Liposomes; Malignant Neoplasms; Marketing; Measurement; Measures; Mediating; Metabolism; Modality; Modeling; Mus; Mutagenesis; Nebraska; Nuclear; Nucleotide Excision Repair; Operative Surgical Procedures; Oregon; Organ Transplantation; Orphan Drugs; Oryctolagus cuniculus; Pathway interactions; Pharmaceutical Preparations; Pharmacology and Toxicology; Phase; Phase I Clinical Trials; Plant Roots; Preclinical Testing; Premalignant; Prevention; Prevention strategy; Process; Production; Protocols documentation; Pyrimidine Dimers; Research; Research Institute; Risk; Risk Factors; Rodent Model; Safety; Secure; Series; Services; Simulate; Skin; Skin Cancer; Skin Carcinoma; Small Business Technology Transfer Research; Solutions; Squamous cell carcinoma; Sun Exposure; Sunlight; System; Technology; Technology Transfer; Testing; Time; Tissues; Toxic effect; Toxicology; Transplant Recipients; Ultraviolet Rays; United States; Universities; Virus; absorption; analytical method; cancer diagnosis; carcinogenesis; commercialization; cytotoxicity; design; disorder prevention; efficacy testing; enzyme activity; experience; human DNA; improved; keratinocyte; manufacturing facility; manufacturing process; meetings; mouse model; pre-clinical; preclinical study; prevent; programs; public education; repair enzyme; repaired; research and development; restoration; scale up; skin cancer prevention; skin lesion; skin squamous cell carcinoma; sunlight-induced; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Current health care modalities for humans diagnosed with either precancerous actinic keratoses or skin cancers (including basal and squamous cell carcinomas) primarily involve surgical excision of the lesions or chemical or photodynamic burning of the affected tissues. These post-diagnostic treatments are directed to disease management, while disease prevention strategies focus on public education that advocates for limiting sunlight exposures, especially in the first two decades of life. However, with ~1.4 million new cases of skin cancer diagnosed in the United States each year, additional prevention strategies are needed. To address this need, Restoration Genetics, Inc (RGI) has developed and patented technologies activating a second, nuclear- targeted DNA repair pathway, base excision repair, for the removal of the primary DNA lesions caused by sunlight exposure, cyclobutane pyrimidine dimers (CPDs). Using Phase I STTR funding, RGI successfully demonstrated the purification of the critical repair enzyme, chlorella virus pyrimidine dimer DNA glycosylase (Cv-pdg-NLS, RG-101), encapsulation of the enzyme into liposomes, and the successful initiation of rapid repair of CPDs in a human skin model. Building from these data, in collaboration with Oregon Health & Science University, RGI will carry out a series of preclinical studies including cGMP process development, biological efficacy analyses, and commercialization development, all of which culminate in a pre-IND meeting with the FDA. Specifically, RG-101 will be produced and packaged in a large-scale cGMP facility at the University of Nebraska and RG-101 encapsulated in liposomes will be tested for preclinical biological efficacy to 1) activate repair of solar-simulated light in a human skin model, 2) prevent UV-induced carcinogenesis in a rodent model, and 3) reduce tumor frequencies following an initial tumor diagnosis. Additionally, pharmacokinetic and toxicology studies will be designed using rabbit and pig models. These investigations complement well the commercialization plan that targets three markets: 1) individuals who are deficient in the normal DNA repair mechanism for CPD removal (conducted under Orphan Drug Status), 2) organ transplant patients who are highly susceptible to frequent, highly aggressive skin cancers, and 3) individuals with high frequency actinic keratoses and cancers, as well as the general public. Collectively, the data will be presented to the FDA in a pre-IND meeting for guidance in pharmacology and toxicology trials and Phase I human clinical trials. Specifically, in this meeting we will present manufacturing, characterization and encapsulation data, biochemical activities of the enzyme and in vitro efficacy in fully differentiated human skin models, mouse carcinogenesis data, and the design of animal pharmacology and toxicology assessments. PUBLIC HEALTH RELEVANCE: Acute and chronic exposures to sunlight are the primary risk factors for the development of 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.

描述（由申请人提供）：目前诊断为癌前光化性角化病或皮肤癌（包括基底细胞癌和鳞状细胞癌）的人的医疗模式主要包括手术切除病变或化学或光动力烧伤受影响的组织。这些诊断后治疗针对的是疾病管理，而疾病预防战略侧重于公众教育，倡导限制阳光照射，特别是在生命的头二十年。然而，在美国，每年约有140万皮肤癌新病例被诊断出来，因此需要额外的预防策略。为了解决这一需求，修复遗传学公司（RGI）开发了激活第二种核靶向DNA修复途径的专利技术，碱基切除修复，用于去除由阳光照射引起的主要DNA损伤，环丁烷嘧啶二聚体（CPDs）。利用第一阶段STTR资金，RGI成功地纯化了关键的修复酶，小球藻病毒嘧啶二聚体DNA糖基酶（Cv-pdg-NLS, RG-101），将酶包封到脂质体中，并成功地在人体皮肤模型中启动了CPDs的快速修复。基于这些数据，RGI将与俄勒冈健康与科学大学合作开展一系列临床前研究，包括cGMP工艺开发、生物功效分析和商业化开发，所有这些都将在与FDA的ind前会议上达到高潮。具体来说，RG-101将在内布拉斯加州大学（University of Nebraska）的大型cGMP设施中生产和包装，并将在脂质体中封装RG-101进行临床前生物学功效测试：1)在人体皮肤模型中激活太阳模拟光的修复，2)在啮齿动物模型中预防紫外线诱导的致癌作用，以及3)在初步肿瘤诊断后降低肿瘤频率。此外，将使用兔和猪模型设计药代动力学和毒理学研究。这些研究很好地补充了针对三个市场的商业化计划：1)缺乏正常DNA修复机制以去除CPD的个体（在孤儿药状态下进行），2)对频繁，高度侵袭性皮肤癌高度敏感的器官移植患者，3)高频率光化性角化病和癌症的个体，以及公众。总的来说，这些数据将在ind前会议上提交给FDA，以指导药理学和毒理学试验以及I期人体临床试验。具体来说，在这次会议上，我们将介绍该酶的制造、表征和封装数据、生化活性和在完全分化的人类皮肤模型中的体外功效、小鼠致癌数据，以及动物药理学和毒理学评估的设计。