Quantitative Test of the Success/Reduction of Harm of Smoking Cessation Treatment

戒烟治疗成功/减少危害的定量测试

• 批准号: 8712187
• 负责人: Terry W Osborn
• 金额: $ 20.22万
• 依托单位: BEHAVIORAL DIAGNOSTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-15 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8712187
• 关键词: Abstinence; Algorithms; Aryl Hydrocarbon Receptor; Behavioral; Biological Markers; Blinded; Bupropion; Carbon Monoxide; Characteristics; Cigarette; Client; Clinical; Clinical Assessment Tool; Consumption; Cotinine; DNA; DNA Methylation; Detection; Development; Diagnostic; Effectiveness; Epigenetic Process; Exhalation; Feedback; Fingers; Genes; Genetic; Goals; Grant; Half-Life; Harm Reduction; Hour; Insurance; Intervention; Laboratories; Lead; Legal patent; Marketing; Masks; Measures; Medical; Methods; Methylation; Morbidity - disease rate; Nicotine; Patient Self-Report; Patients; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase II Clinical Trials; Polymerase Chain Reaction; Positive Reinforcements; Process; Publishing; Relapse; Research; Saliva; Salivary; Secondary to; Serum; Small Business Innovation Research Grant; Smoking; Techniques; Technology; Testing; Time; United States; Venipunctures; Withholding Treatment; Work; base; cigarette smoking; commercialization; community setting; demethylation; drug development; effective therapy; evidence base; experience; innovation; mortality; next generation; nicotine gum; nicotine patch; nicotine replacement; programs; prospective; public health relevance; response; smoking cessation; success; therapy development; urinary; varenicline

DESCRIPTION (provided by applicant): Cigarette smoking is the most common preventable cause of morbidity and mortality in the United States. Over the past 20 years, several effective treatments, including varenicline, bupropion and nicotine replacement treatments (NRT, such as nicotine gum or patches) have been developed. Despite significant efforts, the overall success of these treatments for smoking cessation is about 10%. Although there are number of potential barriers to increasing the success rate of these treatments, one of the most vexing is the lack of methods to objectively quantify treatment success/reduction of harm and provide evidence-based positive feedback to patients. Developing, validating, and commercializing this next-generation technology to exactly quantify the amount of smoking cessation success/harm reduction is Behavioral Diagnostic's overall goal for this multi-phase SBIR study. Currently, two biomarkers of smoking- exhaled carbon monoxide (CO) and (serum, salivary or urinary) cotinine levels exist, but both of these biomarkers have significant limitations as indicators of smoking cessation. Exhaled CO is only useful for detecting smoking within ~12 hours of last use while cotinine levels are insensitive to more remote smoking and are obscured by the use of NRT agents because the nicotine in these agents is also metabolized to cotinine. The latter is a particular problem because the vast majority of patients receiving smoking cessation therapy receive NRT as a primary or adjunctive therapy. Thus, there is both a large potential market and a great need for the development of a new biomarker of smoking that could serve as a more effective clinical assessment tool or be used by pharmaceutical companies to quantify the reduction of harm afforded by the use of a new medication or intervention. Over the past two years, we, and others, have repeatedly demonstrated that demethylation of cg05575921, a CpG residue in the aryl hydrocarbon receptor repressor gene (AHRR) is a sensitive measure of smoking. More recently, we have shown that this methylation at cg05575921 reverts to baseline after cessation of smoking. In this Phase I application, we will use our recently developed real time polymerase chain reaction (RTPCR) test to develop an algorithm describing the relationship of smoking cessation to the reversion of the AHRR methylation signature in DNA from obtained by three methods: venipuncture, easy-to- do finger sticks (i.e. no phlebotomist needed) and easy-to-obtain saliva. The effort will be led by Dr. Terry Osborn, an experienced BioPharma Executive who is also leading our commercialization process, and Drs. Philibert and Madan, the co-inventors on the recently granted patent, who have extensive published experience in the clinical, genetic and epigenetic characteristics of smoking. As a direct result o this project we will develop a formula describing the relationship of abstinence to re-methylation at cg05575921 that can be formally tested in a prospective, blinded Phase II trial of the first epigenetic test for quantitatively determining the success of smoking cessation therapy.

描述（由申请人提供）：吸烟是美国最常见的可预防的发病和死亡原因。在过去的20年里，已经开发出了几种有效的治疗方法，包括伐尼克兰、安非他酮和尼古丁替代治疗（NRT，例如尼古丁口香糖或贴片）。尽管付出了巨大的努力，但这些戒烟治疗的总体成功率约为10%。尽管提高这些治疗的成功率存在许多潜在障碍，但最令人烦恼的是缺乏客观量化治疗成功/减少伤害并向患者提供基于证据的积极反馈的方法。开发，验证和商业化这种下一代技术，以准确量化戒烟成功/危害减少的数量，是行为诊断公司这项多阶段SBIR研究的总体目标。 目前，存在两种吸烟的生物标志物-呼出的一氧化碳（CO）和（血清、唾液或尿）可替宁水平，但这两种生物标志物作为戒烟的指标都具有显著的局限性。呼出的CO仅可用于检测末次使用后约12小时内的吸烟情况，而可替宁水平对更远距离的吸烟不敏感，并且因使用NRT药物而变得模糊，因为这些药物中的尼古丁也代谢为可替宁。后者是一个特别的问题，因为绝大多数接受戒烟治疗的患者接受NRT作为主要或辅助治疗。因此，存在巨大的潜在市场，并且非常需要开发新的吸烟生物标志物，其可以用作更有效的临床评估工具或由制药公司用于量化由使用新药物或干预所提供的危害的减少。 在过去的两年里，我们和其他人反复证明，去甲基化的cg 05575921，在芳烃受体阻遏基因（AHRR）的CpG残基是一个敏感的措施吸烟。最近，我们发现cg 05575921的甲基化在戒烟后恢复到基线水平。在本I期申请中，我们将使用我们最近开发的真实的时间聚合酶链反应（RTPCR）测试来开发一种算法，该算法描述戒烟与通过三种方法获得的DNA中AHRR甲基化特征的逆转之间的关系：静脉穿刺，易于进行的手指针刺（即不需要抽血者）和易于获得的唾液。这项工作将由经验丰富的BioPharma执行官Terry奥斯本博士领导，他也是我们商业化进程的领导者，Philibert博士和Madan博士是最近授予的专利的共同发明人，他们在吸烟的临床，遗传和表观遗传特征方面拥有丰富的出版经验。作为该项目的直接结果，我们将开发一个描述戒烟与cg 05575921处再甲基化的关系的公式，该公式可以在第一个表观遗传学测试的前瞻性、盲态II期试验中正式测试，以定量确定戒烟治疗的成功。