A Quantitative Epigenetic Test for Guiding Smoking Cessation Therapy

在美国，吸烟是最常见的可预防的致病和死亡原因。每年， 吸烟导致超过45万美国人过早死亡，并造成2000亿美元的经济损失。 有效的治疗是可能的，但实施的障碍限制了戒烟的成功率 一般人口增加到5%左右。值得注意的是，基于奖励的激励性戒烟方法可以增加两倍 或者是那个糟糕的应答率的四倍。但它们的实施受到一些因素的阻碍-大多数 重要的是，缺乏一个好的生物标记物来量化卷烟消费的减少或减少 危害(RIH)。 在之前一个非常成功的R43项目中，我们证明了cg05575921处的甲基化 我们的烟雾信号测试，随着成功戒烟和DNA的增加而增加 Cg05575921的甲基化可靠地区分了不吸烟者和吸烟者(AUC为0.99)，以及2) Cg05575921的甲基化回归为戒烟成功的函数。然而， 我们的数据是不完整的，因为在这项第一阶段研究中使用的队列在大小和种族多样性方面有限。 在这个第二阶段的项目中，我们将确认这些发现，并将其扩展为更具代表性的 填充并开发符合CLIA的流程，这些流程可用于将此第一阶段的发现转化为FDA 经批准的用于监测戒烟情况的数字微滴聚合酶链式反应(DdPCR)试验(也称为烟雾信号™)。 在这个第二阶段的项目中，我们将收集和描述250名不同种族的受试者，因为他们 接受戒烟治疗。然后我们将确定它们的DNA甲基化是吸烟的结果 戒烟成功。在此基础上，我们将产生一条可用于生物标记物引导的精炼回归曲线。 治疗和创建其他数据，以供FDA提交我们的检测。我们的项目将有很高的商业和 临床影响，因为烟雾信号™检测可以为改进的临床范例奠定基础 用于治疗吸烟，并成为公民(例如保险公司)吸烟的明确指标 等)对吸烟状况的评估。我们的计划非常可行，因为行为诊断公司控制了 相关知识产权，临床表观遗传学专业知识，可操作的ddPCR甲基化检测， 接触有经验的临床医生的受试者和工作人员。这是创新的，因为表观遗传技术没有 但已被纳入行为医学。该项目将由我们的首席执行官Rob博士领导 他是国际知名的临床表观遗传学专家。他将得到一支共同-- 在各自领域处于领先地位的调查人员。我们得到了Bio-Rad的帮助，这家公司将从我们的 成功。作为直接结果，我们将创建数据来支持将检测提交给FDA和 临床医生评估戒烟成功与否的知识库。

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.