Stem Cell Therapy, Inflammation and Treatment Response inAlcoholism-Depression Comorbidity

干细胞疗法、酒精中毒抑郁症合并症的炎症和治疗反应

• 批准号: 9380069
• 负责人: CHARLES B NEMEROFF
• 金额: $ 69.04万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9380069
• 关键词: Address; Alcohol consumption; Alcoholism; Alcohols; Allogenic; Anhedonia; Anti-Inflammatory Agents; Anti-inflammatory; Biological Markers; Blood specimen; C-reactive protein; Cell Therapy; Clinical; Clinical Trials; Cognition; Collection; Comorbidity; Complex; Congestive Heart Failure; Disease; Epigenetic Process; Essential Hypertension; Etiology; Exhibits; FDA approved; Fostering; Genetic Polymorphism; Heavy Drinking; Human; Immune; Inflammation; Inflammatory; Infusion procedures; Intervention; Major Depressive Disorder; Measures; Mediating; Mediator of activation protein; Medical; Mental Depression; Mesenchymal Stem Cells; Modality; Mood Disorders; Morbidity - disease rate; Myocardial Infarction; Names; Outcome; Outcome Study; Pathogenesis; Pathway interactions; Patients; Perceived quality of life; Pharmaceutical Preparations; Pharmacotherapy; Placebos; Play; Population; Quality of life; Recurrence; Reporting; Research; Role; Severities; Stroke; Syndrome; Testing; Therapeutic; Universities; alcohol comorbidity; alcohol exposure; alcohol use disorder; clinical practice; cognitive performance; comorbid depression; craving; cytokine; depressive symptoms; effective therapy; evidence base; experience; follow-up; immune activation; indexing; inflammatory marker; medical schools; novel; pediatric trauma; problem drinker; randomized placebo controlled trial; response; stem cell therapy; successful intervention; suicidal behavior; treatment effect; treatment response

Abstract Alcohol use disorder (AUD) with comorbid major depression (MD) is among the most frequent and serious conditions encountered in clinical practice, for which effective treatment interventions are currently limited. Activation of pro-inflammatory cytokines and pathways are emerging as key pathophysiological factors in the etiology of both alcoholism and major depression. Although immune and inflammatory mechanisms have been studied to a considerable extent in alcoholism and major depression separately, patients with co-occurring alcoholism and major depression are most likely to exhibit substantial inflammation. Pro-inflammatory mechanisms appear to play a bidirectional role in both depression and alcoholism and may underlie the limited treatment response reported in clinical trials. The lack of previously effective treatments demands new intervention modalities and different treatment targets targeting mechanisms underlying such comorbidity. We hypothesize that increased inflammation in these patients represents a major factor fostering decreased treatment response. Thus, patients with comorbid AUD and MD represent an ideal group to test the effect of a potent anti-inflammatory intervention. We propose to use allogeneic human mesenchymal stem cell (ahMSC) therapy, a highly novel treatment pioneered at the University of Miami Miller School of Medicine, to treat a variety of inflammatory conditions. This treatment has been shown to be safe and well-tolerated in a variety of medical disorders and exerts a robust and sustained anti-inflammatory effect. We plan to test the effects of ahMSCs on inflammation and on alcohol and depression outcomes in patients with comorbid AUD and recurrent MD (AUD- MD) preselected for the presence of high inflammatory markers (hsCRP>3 mg/L). Our study has the following Specific Aims: Aim 1. To examine the effects of a single ahMSC infusion on inflammation, as assessed by C- Reactive Protein (CRP) concentrations in a 12-week randomized, placebo-controlled trial in 80 MD-AUD patients (40 active infusion, 40 placebo) all preselected for the presence of inflammation. Aim 2. To examine the effects of the reduction in CRP and other inflammatory markers associated with ahMSC therapy on clinician- administered measures of the severity of alcohol use (TLFB-% heavy drinking days) and depression (MADRS) and global clinical functioning (CGI). Aim 3. To examine the direct (reduction in CRP and other inflammatory biomarkers) and indirect (reduction in alcohol use and depression) effects of ahMSC therapy on secondary study outcomes including, craving, cognition, everyday functioning and perceived quality of life. Aim 4. Our exploratory aim includes assessment of the mediating role of childhood trauma and assessment of the persistence of treatment effects over the one year follow-up period, with collection of blood samples to explore the role of inflammation related-polymorphisms and epigenetics in treatment response. If successful, this treatment would represent a paradigm shift in treating AUD-MD comorbidity and will have a significant impact on the field of therapeutics for other complex conditions in which altered inflammatory mechanisms play a substantial role in their pathogenesis.

抽象的 酒精使用障碍 (AUD) 合并重度抑郁症 (MD) 是最常见和最严重的疾病之一 临床实践中遇到的情况，目前有效的治疗干预措施有限。 促炎细胞因子和通路的激活正在成为关键的病理生理因素 酗酒和重度抑郁症的病因学。尽管免疫和炎症机制已被 分别对酗酒和重度抑郁症进行了相当大的研究，同时发生的患者 酗酒和重度抑郁症最有可能表现出严重的炎症。促炎性 机制似乎在抑郁症和酗酒中发挥双向作用，并且可能是有限的基础 临床试验中报告的治疗反应。由于缺乏先前有效的治疗方法，需要新的治疗方法 针对此类合并症潜在机制的干预方式和不同治疗目标。我们 假设这些患者的炎症增加是导致炎症减少的一个主要因素 治疗反应。 因此，患有 AUD 和 MD 共病的患者是测试治疗效果的理想群体。 有效的抗炎干预。我们建议使用同种异体人类间充质干细胞（ahMSC） 疗法是迈阿密大学米勒医学院首创的一种高度新颖的疗法，可治疗多种 炎症状况。这种治疗方法已被多种医学证明是安全且耐受性良好的 疾病并发挥强大而持续的抗炎作用。我们计划测试ahMSCs对 共病 AUD 和复发性 MD 患者（AUD- MD) 预选是否存在高炎症标志物 (hsCRP>3 mg/L)。我们的研究有以下几点 具体目标： 目标 1. 通过 C- 评估，检查单次 ahMSC 输注对炎症的影响 一项针对 80 名 MD-AUD 患者进行的为期 12 周的随机安慰剂对照试验中的反应蛋白 (CRP) 浓度 （40 名活性输注剂，40 名安慰剂）均根据炎症的存在进行预选。目标 2. 检查效果 与 ahMSC 治疗相关的 CRP 和其他炎症标志物的降低对临床医生的影响 管理饮酒严重程度（TLFB-% 酗酒天数）和抑郁症 (MADRS) 和整体临床功能（CGI）。目标 3. 检查 CRP 和其他炎症的直接（减少） ahMSC 治疗对二次研究的生物标志物）和间接（减少饮酒和抑郁）影响 结果包括渴望、认知、日常功能和感知的生活质量。目标 4. 我们的探索 目标包括评估童年创伤的中介作用以及评估童年创伤的持续性 一年随访期间的治疗效果，通过采集血样来探讨其作用 治疗反应中炎症相关的多态性和表观遗传学。如果成功的话，这种治疗将 代表了治疗 AUD-MD 合并症的范式转变，并将对该领域产生重大影响 针对其他复杂病症的治疗，其中改变的炎症机制在其中发挥重要作用 他们的发病机制。