DNA Repair Enzymes for the Prevention of Skin Cancer

用于预防皮肤癌的 DNA 修复酶

基本信息

批准号：
8738036
负责人：
AMANDA K MCCULLOUGH
金额：
$ 3.62万
依托单位：
RESTORATION GENETICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-03-01 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8738036
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

项目摘要

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.

描述（由申请人提供）：当前针对诊断为癌性活化性角膜结构或皮肤癌（包括基础和鳞状细胞癌）的人类的医疗保健方式主要涉及对受影响组织的病变或化学或光动力燃烧的手术切除。这些诊断后治疗是针对疾病管理的，而疾病预防策略则集中在倡导限制阳光暴露的公共教育上，尤其是在生命的前二十年。但是，每年在美国诊断出约140万例新的皮肤癌病例，需要其他预防策略。为了满足这一需求，Restoration Genetics，Inc（RGI）已开发并获得了专利的技术，该技术激活了第二种核靶向DNA修复途径，基础切除修复，以去除由阳光暴露，环丁烷吡啶胺（CPDS）引起的主要DNA病变。使用I期STTR资金，RGI成功证明了临界修复酶，小球藻病毒病毒嘧啶二聚体DNA糖基酶（CV-PDG-NLS，RG-101），酶在脂质体中的封装，脂质体中的脂质体和人类皮肤中CPD的快速修复的成功开始。 RGI与俄勒冈州健康与科学大学合作，将从这些数据中构建，将进行一系列临床前研究，包括CGMP流程开发，生物效率分析和商业化开发，所有这些都在与FDA的预先会议中达到了最终结论。 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.此外，将使用兔子和猪模型设计药代动力学和毒理学研究。这些调查很好地补充了针对三个市场的商业化计划：1）缺乏正常DNA修复机制去除CPD的人（在孤儿药物状态下进行），2）有机移植患者，他们高度易于频繁，高度侵略性的皮肤癌，3）患有高频率的正常性角膜蛋白酶和cancersose和cancers和cancers and Cancers和General Plisase以及将军。总的来说，数据将在一次预先开会的药理学和毒理学试验指导和I期人类临床试验的指导中提交FDA。具体而言，在本次会议上，我们将介绍在完全分化的人类皮肤模型，小鼠癌变数据以及动物药理学和毒理学评估的设计中，酶的制造，表征和封装数据，酶的生化活性和体外功效。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Effects of physical or fenceline boar exposure and exogenous gonadotropins on puberty induction and subsequent fertility in gilts.

物理或栅栏公猪暴露和外源性促性腺激素对后备母猪青春期诱导和随后生育力的影响。

DOI：
10.1093/jas/skab348
发表时间：
2021
期刊：
Journal of animal science
影响因子：
3.3
作者：
Knox,RobertV;Arend,LidiaS;Buerkley,AshleyL;Patterson,JenniferL;Foxcroft,GeorgeR
通讯作者：
Foxcroft,GeorgeR