A Quantitative Epigenetic Test for Guiding Smoking Cessation Therapy

吸烟是美国最常见的可预防的发病和死亡原因。每年， 吸烟导致超过45万美国人过早死亡和2000亿美元的经济损失。 有效的治疗是可能的，但其实施的障碍限制了戒烟的成功率， 一般人口的5%左右。值得注意的是，基于奖励的激励戒烟方法可以增加两倍 或者是原来的四倍但它们的实施受到许多因素的阻碍， 重要的是，缺乏良好的生物标志物来量化香烟消费的减少或吸烟的减少， 伤害（RIH）。 在之前非常成功的R43项目中，我们证明了cg 05575921处的甲基化，如通过 我们的吸烟特征分析，作为成功戒烟的函数而增加， cg 05575921处的甲基化可靠地区分非吸烟者与吸烟者（AUC为0.99），以及2） CG 05575921处的甲基化回归到作为戒烟成功的函数的均值。然而，在这方面， 我们的数据是不完整的，因为在这个I期研究中使用的队列在规模和种族多样性上是有限的。 在这个第二阶段的项目中，我们将确认这些发现，并将其扩展到一个更具普遍代表性的 人口和开发CLIA合规流程，可用于将第一阶段的发现转化为FDA 经批准的数字液滴PCR（ddPCR）检测（又名Smoke Signature™），用于监测戒烟。 在这个第二阶段的项目中，我们将收集和描述一个由250名受试者组成的种族多样化的群体， 接受戒烟治疗。然后我们将确定他们的DNA甲基化作为吸烟的函数 停止成功。由此，我们将产生可用于生物标志物引导的精确的回复曲线。 治疗，并为FDA提交我们的检测创建其他数据。我们的项目将有很高的商业和 临床影响，因为Smoke Signature™测定可以为改进临床范式奠定基础 用于治疗吸烟，并成为民间（如保险公司）吸烟的明确指标 等）评估吸烟状况。我们的计划是非常可行的，因为行为诊断的控制， 相关知识产权，临床表观遗传学专业知识，可操作的ddPCR甲基化测定， 接触受试者和经验丰富的临床医生的工作人员。它是创新的，因为表观遗传技术没有 还被纳入行为医学。该项目将由我们的首席执行官Rob博士领导 Philibert博士是国际知名的临床表观遗传学专家。他将得到一个团队的协助， 他们是各自领域的领导者。我们得到了Bio-Rad的帮助，这家公司将从我们的产品中获益。 成功作为直接结果，我们将创建数据以支持向FDA提交检测试剂盒， 为临床医生评估戒烟成功与否提供知识基础。

Smoking is the most common preventable cause of morbidity and mortality in the United States. Each year, smoking causes the premature death of over 450,000 Americans and $200 billion of economic damage. Effective treatment is possible but barriers to its implementation limits the success rate of smoking cessation in the general population to about 5%. Notably, reward based incentive smoking cessation methods could triple or quadruple that abysmal response rate. But their implementation is hindered by a number of factors-most importantly, the lack of a good biomarker for quantifying the decrease of cigarette consumption or reduction in harm (RIH). In a very successful prior R43 project, we demonstrated that methylation at cg05575921, as quantified by our Smoke Signature assay, increases as a function of successful smoking cessation and that DNA methylation at cg05575921 reliably distinguishes non-smokers from smokers (with an AUC of 0.99), and 2) methylation at cg05575921 regresses to mean as a function of the success of smoking cessation. However, our data are incomplete since the cohorts used in this Phase I study were limited in size and ethnic diversity. In this Phase II project, we will confirm and extend those findings into a more generally representative population and develop CLIA compliant processes that can be used to translate this Phase I finding into FDA approved, digital droplet PCR (ddPCR) test (a.k.a Smoke Signature™) for monitoring of smoking cessation. In this Phase II project, we will collect and characterize an ethnically diverse group of 250 subjects as they undergo smoking cessation therapy. We will then determine their DNA methylation as a function of smoking cessation success. From this, we will produce a refined reversion curve that can be used in biomarker guided therapy and create other data for the FDA submission of our assay. Our project will have high commercial and clinical impact because the Smoke Signature™ assay could create the basis for an improved clinical paradigm for the treatment of smoking and be an unambiguous indicator of smoking for civil (e.g. insurance companies etc) assessments of smoking status. Our plan is highly feasible because of Behavioral Diagnostic's control of relevant intellectual property, expertise in clinical epigenetics, an operational ddPCR methylation assay, access to subjects and staff of experienced clinicians. It is innovative because epigenetic techniques have not yet been incorporated into behavioral medicine. The project will led by our Chief Executive Officer, Dr. Rob Philibert, who is an internationally known expert in clinical epigenetics. He will be assisted by a team of co- investigators who are leaders in their fields. We are aided by Bio-Rad, a company that stands to gain from our success. As a direct result, we will create the data to support the submission of the assay to the FDA and a knowledge base for clinicians to assess the success of smoking cessation.