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

描述(申请人提供)：在美国，吸烟是最常见的可预防的致病和死亡原因。在过去的20年里，已经开发了几种有效的治疗方法，包括varenicline、安非他酮和尼古丁替代疗法(NRT，如尼古丁口香糖或贴片)。尽管付出了巨大的努力，但这些戒烟疗法的总体成功率约为10%。虽然提高这些治疗的成功率有许多潜在的障碍，但最令人烦恼的是缺乏客观量化治疗成功/减少伤害的方法，并向患者提供基于证据的积极反馈。开发、验证和商业化这项下一代技术以准确量化戒烟成功/减少危害的数量是行为诊断公司在这项多阶段SBIR研究中的总体目标。目前，存在吸烟呼出的一氧化碳(CO)和(血清、唾液或尿液)可替宁水平两种生物标志物，但这两种生物标志物作为戒烟指标都有很大的局限性。呼出的CO仅在最后一次使用后12小时内检测到吸烟，而可替宁水平对更远的吸烟不敏感，并被NRT试剂的使用所掩盖，因为这些试剂中的尼古丁也被代谢为可替宁。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都将NRT作为主要或辅助治疗。因此，开发一种新的吸烟生物标志物既有巨大的潜在市场，又有很大的需求，可以作为一种更有效的临床评估工具，或被制药公司用来量化使用新药物或干预措施所带来的伤害减少。在过去的两年里，我们和其他人反复证明，cg05575921去甲基化是吸烟的一个敏感指标。cg05575921是芳香烃受体抑制基因(AHRR)中的一个CpG残基。最近，我们发现在戒烟后cg05575921的这种甲基化恢复到基线水平。在这一阶段的应用中，我们将使用我们最近开发的实时聚合酶链式反应(RTPCR)测试来开发一种算法，描述戒烟与DNA中AHRR甲基化签名逆转的关系，该DNA甲基化签名是通过三种方法获得的：静脉穿刺法、易于操作的手指棒(即不需要抽血者)和易于获得的唾液。这项工作将由泰瑞·奥斯本博士领导，他是一位经验丰富的生物制药高管，也是我们的商业化进程的领导者，还有菲利伯特博士和马丹博士，他们是最近授予的专利的共同发明人，他们在吸烟的临床、遗传和表观遗传学特征方面拥有丰富的已发表经验。作为这个项目的直接结果，我们将开发一个公式，描述戒烟与cg05575921基因重新甲基化的关系，该公式可以在第一次表观遗传学测试的前瞻性、盲目第二阶段试验中正式测试，以定量确定戒烟治疗的成功。

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.