DNA Repair Enzymes for the Prevention of Skin Cancer

描述(由申请人提供)：目前被诊断患有癌前光化性角化病或皮肤癌(包括基底细胞癌和鳞癌)的人的医疗保健模式主要包括手术切除病变或对受影响的组织进行化学或光动力烧伤。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倡导限制阳光暴露的公共教育，特别是在生命的头20年。然而，美国每年约有140万新确诊的皮肤癌病例，需要额外的预防策略。为了满足这一需求，恢复遗传学公司(RGI)开发了激活第二个核靶向DNA修复途径-碱基切除修复-的技术并获得了专利，用于移除阳光照射引起的初级DNA损伤，环丁烷嘧啶二聚体(CPDS)。利用第一阶段STTR资金，RGI成功地证明了关键修复酶小球藻病毒嘧啶二聚体DNA糖基酶(CV-PDG-NLS，RG-101)的纯化，将该酶包裹到脂质体中，并在人体皮肤模型中成功地启动了CPD的快速修复。在这些数据的基础上，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IND前与FDA举行会议。具体地说，RG-101将在内布拉斯加州大学的一个大型cGMP设施中生产和包装，并且将测试包裹在脂质体中的RG-101的临床前生物学功效，以1)激活人体皮肤模型中的太阳能模拟光的修复，2)防止紫外线诱导啮齿动物模型的致癌，以及3)在初步肿瘤诊断后降低肿瘤频率。此外，药代动力学和毒理学研究将使用兔和猪的模型进行设计。这些调查很好地补充了针对三个市场的商业化计划：1)缺乏去除CPD的正常DNA修复机制的个人(在孤儿药物状态下进行)，2)器官移植患者，他们非常容易患上频繁的、高度侵袭性的皮肤癌，以及3)高频率光化性角化病和癌症的个人，以及普通公众。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第一阶段人类临床试验。具体地说，在这次会议中，我们将介绍制造、表征和封装数据、酶的生化活性和在完全分化的人类皮肤模型中的体外疗效、小鼠致癌数据，以及动物药理学和毒理学评估的设计。

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.