CTRIP: Treatment of Sickle Cell Crisis with inhibitors of NKT cell activation

描述(由申请人提供)：这一阶段的旅行申请将使治疗镰状细胞病(SCD)的新疗法的第二阶段临床试验在两年内完成。我们建议的基础是我们最近的发现，不变NKT(INKT)细胞在SCD小鼠的组织炎症和损伤中起重要作用。这些细胞在SCD患者的血液中数量增加并被激活。腺苷A2A受体(A2AR)高表达于iNKT细胞，A2A激动剂抑制iNKT细胞的激活，减轻SCD小鼠的组织损伤。我们假设A2a激动剂将减少患者血液中的炎性生物标志物，并缩短痛苦的SCD危象的持续时间和严重程度。我们将使用A2A激动剂Lexiscan进行试点安全性和生物标记物研究，Lexiscan已被临床批准为药物应激剂。此外，我们将在小鼠身上评估其他抗iNKT细胞药物候选，这些候选药物可以在随后的临床研究中作为Lexiscan的替代品进行测试。我们组建了一支由来自三个机构的临床和基础研究人员组成的专家团队。这些人包括发起羟基尿素疗法的SCD治疗思想领袖David Nathan医学博士，以及其他四名临床科学家，他们指导成人和青少年SCD诊所，这些诊所将为华盛顿大学或哈佛附属医院的患者提供这些研究：Joshua field博士、Michael DeBaun医生、Maureen Okam医生和Mathew Heeney医生。人体血液生物标记物的分析将在拉霍亚过敏和免疫学研究所(LIAI)使用尖端的流式细胞术技术进行，并由Basic Co-Pi，Joel Linden，PhD博士监督，他发现iNKT细胞加剧SCD小鼠的组织损伤，iNKT细胞被A2A激动剂抑制。将帮助评估iNKT细胞功能的联合研究人员是两位世界领先的NKT细胞权威，LIAI的Mitch Kronenberg博士和Mark Exley或哈佛大学的Mitch Kronenberg博士。第一阶段行程的目的如下：临床前研究：目的1是确定减轻NY1DD(SCD)小鼠肝脏和肺部炎症和损伤以及减少白细胞激活所需的Lexiscan的最佳剂量和持续时间；目的2是评估抗iNKTCR抗体和新型iNKT受体糖脂拮抗剂，以确定它们是否为可减轻SCD小鼠组织损伤的候选治疗药物。SCD的初步临床研究：目的3是在输注Lexiscan 12h的情况下进行小剂量递增研究，以确定SCD患者的最大耐受量(MTA)；目标4是评估输液24小时期间MTD的安全性；目标5是评估MTD在成人和青少年患者痛苦危象期间的安全性。在这些研究中，我们还将检测患者血液中的炎症生物标志物。这一阶段一次旅行方案的主要目标是为Lexiscan治疗镰状细胞疼痛危机的第二阶段临床试验做准备。第二个目标是为Lexiscan治疗急性胸腔综合征的临床试验做准备，并准备好抗iNKT细胞受体抗体和糖脂拮抗剂，用于未来对SCD的临床评估。 公共卫生相关性：镰状细胞病(SCD)是美国最常见的遗传性血液疾病，影响约8万人(每600名非裔美国人中有1人)。它会导致短寿命、疼痛和多器官衰竭。我们发现了一种新的抗炎方法，可以有效地治疗小鼠的SCD，我们计划在SCD患者中评估这种新的治疗方法。

DESCRIPTION (provided by applicant): This stage one TRIP application will enable a phase II clinical trial of a new therapy to treat sickle cell disease (SCD) in two years. The basis of our proposal is our recent discovery that invariant NKT (iNKT) cells contribute importantly to tissue inflammation and injury in SCD mice. These cells are increased in number and activated in the blood of patients with SCD. Adenosine A2A receptors (A2AR) are highly expressed on iNKT cells and A2A agonists inhibit iNKT cell activation and reduce tissue damage in SCD mice. We hypothesize that A2A agonists will reduce inflammatory biomarkers in patient blood and reduce the duration and severity of painful SCD crises. We will use the A2A agonist, Lexiscan, that is clinically approved as a pharmacological stress agent, to conduct pilot safety and biomarker studies. In addition we will evaluate in mice additional anti-iNKT cell drug candidates that can be tested as alternatives to Lexiscan in subsequent clinical studies. We have assembled an expert team of clinical and basic investigators from three institutions. These include the Co-PI, David Nathan, M.D., a thought leader in SCD treatment who originated hydroxyurea therapy; and four other clinician scientists who direct adult and juvenile SCD clinics that will provide patients for these studies at Washington U., or Harvard-affiliated hospitals: Drs Joshua Field, Michael DeBaun, Maureen Okam and Mathew Heeney. The analysis of human blood for biomarkers will be conducted at the La Jolla Institute of Allergy and Immunology (LIAI) using cutting-edge flow cytometric techniques and overseen by the Basic Co-PI, Joel Linden, PhD, who discovered that iNKT cells exacerbate tissue injury in SCD mice and that iNKT cells are inhibited by A2A agonists. Co-investigators who will help evaluate iNKT cell function are two of the world's leading authorities on NKT cells, Drs. Mitch Kronenberg of LIAI and Mark Exley or Harvard. The aims for this stage I TRIP are summarized as follows: Preclinical studies: Aim 1 is to determine the optimal dose and duration of Lexiscan needed to reduce liver and lung inflammation and injury and reduce leukocyte activation in NY1DD (SCD) mice; Aim 2 is to evaluate anti-iNKTCR antibodies and novel glycolipid antagonists of iNKT receptors to determine if they are therapeutic candidates that can reduce tissue injury in SCD mice. Preliminary SCD clinical studies: Aim 3 is to conduct a small dose escalation study with Lexiscan infused for 12 h to determine the maximal tolerated dose (MTA) in SCD patients; Aim 4 is to evaluate the MTD for safety during infusion for 24 h; Aim 5 is to evaluate the MTD for safety in adult and juvenile patients during painful crises. During these studies we also will examine biomarkers of inflammation in the blood of patients. The primary goal of this stage one TRIP proposal is to prepare for a phase 2 clinical trial of Lexiscan for sickle cell painful crisis. Secondary goals are to prepare for a clinical trial of Lexiscan for acute chest syndrome, and to ready anti-iNKT cell receptor antibodies and glypolipid antagonists for future clinical evaluation in SCD. PUBLIC HEALTH RELEVANCE: Sickle cell disease (SCD) is the most common genetic blood disorder in the United States, affecting about 80,000 people (1 of every 600 African Americans). It causes short life span, pain and multi-organ failure. We have discovered a new anti-inflammatory approach to effectively treat SCD in mice and we plan to evaluate this new therapy in patients with SCD.