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

CTRIP：用 NKT 细胞活化抑制剂治疗镰状细胞危机

• 批准号: 7940964
• 负责人: Joel M. Linden
• 金额: $ 94.88万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7940964
• 关键词: Adenosine; Adenosine A2A Receptor; Adhesions; Adolescent; Adult; Affect; African American; Agonist; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Antigen Presentation; Antigens; Biological Markers; Birth; Blood; Blood Vessels; CD1 Antigens; Cause of Death; Cell Line; Cell physiology; Cells; Childhood; Clinic; Clinical; Clinical Research; Clinical Treatment; Clinical Trials; Clinical Trials Design; Data; Deferoxamine; Dependence; Disease; Doctor of Medicine; Doctor of Philosophy; Dose; Engineering; Enrollment; Ensure; Epithelial Cells; Equilibrium; Fc Receptor; Future; Genetic; Glycolipids; Goals; Hematological Disease; Hospitals; Human; Hypersensitivity; Immunology; Individual; Infarction; Inflammation; Inflammatory; Infusion procedures; Injury; Institutes; Institution; Interleukin-2; Interleukin-4; Investigation; Iron Chelation; Ischemia; Lead; Leukocytes; Lipids; Liver; Longevity; Lung Inflammation; Lymphocyte; Maximum Tolerated Dose; Messenger RNA; Morbidity - disease rate; Mus; Organ; Organ failure; Pain; Patients; Phase II Clinical Trials; Platelet Activation; Play; Population; Process; Purinergic P1 Receptors; Receptor Activation; Receptor Cell; Receptor Signaling; Recurrence; Regulation; Reperfusion Injury; Reperfusion Therapy; Research Infrastructure; Research Personnel; Role; Safety; Scientist; Severities; Sickle Cell; Sickle Cell Anemia; Staging; Stress; Stroke; T-Cell Receptor; Techniques; Testing; Therapeutic; Tilia; Time; Tissues; United States; Washington; acute chest syndrome; arm; authority; base; cell type; drug candidate; efficacy testing; experience; fundamental research; hydroxyurea; inhibitor/antagonist; leukocyte activation; mortality; neutrophil; novel; preclinical study; public health relevance; receptor; research clinical testing; safety study; sickle cell crisis; subcutaneous; vascular inflammation

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.

描述（由申请人提供）：这一阶段的TRIP申请将使一个新的治疗镰状细胞病（SCD）的II期临床试验在两年内。我们的提议的基础是我们最近发现不变NKT（iNKT）细胞对SCD小鼠的组织炎症和损伤有重要作用。这些细胞在SCD患者的血液中数量增加并被激活。腺苷A2 A受体（A2 AR）在iNKT细胞上高度表达，并且A2 A激动剂抑制iNKT细胞活化并减少SCD小鼠中的组织损伤。我们假设A2 A激动剂将减少患者血液中的炎症生物标志物，并减少疼痛性SCD危象的持续时间和严重程度。我们将使用A2 A激动剂，Leclycan，这是临床批准的药理应激剂，进行试点安全性和生物标志物研究。此外，我们将在小鼠中评估其他抗iNKT细胞候选药物，这些药物可以在后续临床研究中作为LNKT的替代品进行测试。 我们组建了一个由来自三个机构的临床和基础研究人员组成的专家团队。这些包括共同PI，大卫内森，医学博士，他是SCD治疗的思想领袖，首创了羟基脲疗法;另外四名临床科学家指导成人和青少年SCD诊所，为华盛顿大学的这些研究提供患者，或哈佛附属医院：约书亚菲尔德博士、迈克尔·德伯恩博士、莫林·奥卡姆博士和马修·希尼博士。将在拉霍亚过敏和免疫学研究所（LIAI）使用尖端流式细胞术技术进行人血生物标志物分析，并由Basic Co-PI，Joel林登，PhD监督，他发现iNKT细胞会加重SCD小鼠的组织损伤，并且iNKT细胞会受到A2 A激动剂的抑制。将帮助评估iNKT细胞功能的共同研究者是世界上NKT细胞领域的两位主要权威，LIAI的Mitch Kronenberg博士和哈佛的Mark Exley博士。临床前研究：目的1是确定在NY 1DD（SCD）小鼠中减轻肝和肺炎症和损伤以及减少白细胞活化所需的LIPs的最佳剂量和持续时间;目的二是评价抗-iNKTCR抗体和iNKT受体的新型糖脂拮抗剂，以确定它们是否是可以减少SCD中组织损伤的治疗候选物小鼠 初步SCD临床研究：目的3是进行一项小剂量递增研究，输注12小时的Lectin can，以确定SCD患者的最大耐受剂量（MTA）;目的4是评价输注24小时期间的MTD安全性;目的5是评价成人和青少年患者疼痛危象期间的MTD安全性。在这些研究中，我们还将检查患者血液中炎症的生物标志物。TRIP第一阶段提案的主要目标是为Leptin can治疗镰状细胞疼痛危象的第二阶段临床试验做准备。次要目标是为Lebrycan治疗急性胸部综合征的临床试验做准备，并为SCD的未来临床评价准备抗iNKT细胞受体抗体和糖脂拮抗剂。 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80，000人（每600名非洲裔美国人中有1人）。它会导致寿命缩短，疼痛和多器官衰竭。我们已经发现了一种新的抗炎方法来有效地治疗小鼠SCD，我们计划在SCD患者中评估这种新疗法。