Proof-of-Concept Human Laboratory Testing of Novel Drug Candidates Identified by INIA-NeuroImmune

项目摘要 开发具有稳健效应量和良好安全性和耐受性的新型药物是INIA RFA 研究优先。这个翻译项目将通过提供概念验证来应对这一研究挑战 人类实验室测试的前三名神经免疫药物候选人确定为具有治疗 梅菲尔德/法里斯/波诺马列夫博士的“给网络下药”计算 基因组分析和贝尔博士，Blednov/Messing，Crabbe/Ozburn和Lasek的动物模型。药物 用于人体研究的药物将被FDA批准用于其他适应症或可用于IND研究 并将由Mason博士根据INIA神经免疫执行机构的科学优先级进行选择 委员会和安全考虑。药物将在高度标准化、可靠且有效的人体中进行测试 实验室模型告知成瘾周期的三个阶段：戒断/负面影响， 专注/预期和狂欢/中毒，人类实验室结果作为 双盲安慰剂对照临床试验的饮酒结果。每项研究的受试者将为50名非 寻求治疗的男性和女性付费志愿者，符合DSM-5酒精使用障碍标准， 中度（AUD-MS）。研究是随机、双盲和安慰剂对照的。治疗 持续时间至少为1周，并由药物药代动力学指导。主要终点是渴望分数， 对实验室中呈现的体内酒精提示的反应，具有确认的生理结果，以及 饮酒情绪和渴望的自然测量具体目的1：评价神经免疫药物INIA 使用人类实验室模型，当前AUD-MS的付费非寻求治疗志愿者中的候选人 为成瘾周期的三个阶段提供信息。具体目标2：确定潜在的生物标志物 应激和炎症的外周标记物的临床结果（例如，高敏C反应蛋白， 选择的趋化因子，促细胞因子和促细胞因子，和皮质醇）与Dr. Roberto/Roberts/Bajo安全性目的：评价INIA-神经免疫药物的安全性和耐受性 AUD-MS受试者中的候选人，通过EKG、血常规和 以及相对于安慰剂的尿生化、生命体征、体格检查和主观主诉。假设： 检验的总体假设是，相对于安慰剂，通过INIA鉴定的新型候选药物- 神经免疫将显着减弱人类实验室模型对酒精提示的反应， 治疗期间和治疗后1个月随访期间的饮酒、渴望和负面影响。解释 结果：阳性结果将为确定的神经免疫靶点和机制提供临床验证 通过INIA-Neuroimmune，为候选药物的后期测试提供合理的基础， 治疗AUD-MS。

Project Summary The development of novel medications with robust effect sizes and good safety and tolerability is an INIA RFA research priority. This translational project will respond to this research challenge by providing proof-of-concept human laboratory testing of the top three neuroimmune drug candidates identified as having therapeutic potential for alcohol use disorder by Dr. Mayfield/Farris/Ponomarev's “drugging the network” computational genomic analyses and by Drs. Bell's, Blednov/Messing's, Crabbe/Ozburn's and Lasek's animal models. Drugs identified for human study will either be FDA-approved for other indications or available for study under an IND and will be selected by Dr. Mason based on scientific prioritization by the INIA-Neuroimmune Executive Committee and safety considerations. Drugs will be tested in a highly standardized, reliable, and valid human laboratory model informing the three stages of the addiction cycle: withdrawal/negative affect, preoccupation/anticipation, and binge/intoxication, with human laboratory results serving as an analogue for drinking outcomes of double-blind, placebo-controlled clinical trials. Subjects for each study will be 50 non- treatment-seeking male and female paid volunteers who meet DSM-5 criteria for alcohol use disorder of ≥ moderate severity (AUD-MS). Studies are randomized, double-blind, and placebo-controlled. The treatment duration is at least 1-week and guided by drug pharmacokinetics. The primary endpoint is craving scores in response to in vivo alcohol cues presented in the laboratory, with confirmatory physiological outcomes, and naturalistic measures of drinking, mood, and craving. Specific Aim 1: To evaluate INIA-Neuroimmune drug candidates in paid non-treatment-seeking volunteers with current AUD-MS using the human lab model informing targets for the 3 stages of the addiction cycle. Specific Aim 2: To identify potential biomarkers of clinical outcomes in peripheral markers of stress and inflammation (e.g., high-sensitivity C-reactive protein, selected chemokines, pro- and antiinflammatory cytokines, and cortisol) in collaboration with Drs. Roberto/Roberts/Bajo. Safety Aim: To evaluate the safety and tolerability of INIA-Neuroimmune drug candidates in subjects with AUD-MS, as assessed by significant changes from baseline in EKG, routine blood and urine biochemistry, vital signs, physical exam, and subjective complaints relative to placebo. Hypothesis: The overall hypothesis under test in that, relative to placebo, novel drug candidates identified by INIA- Neuroimmune will significantly attenuate responsivity to alcohol cues in the human lab model and reduce drinking, craving, and negative affect during treatment and 1-month of post-treatment follow-up. Interpretation of Results: Positive findings will provide clinical validation of neuroimmune targets and mechanisms identified by INIA-Neuroimmune and provide a rational basis for later phase testing of candidate drugs as potential therapeutics for AUD-MS.