First Clinical Trial of an Anti-Sickling Botanical Drug for Sickle Cell Dise

抗镰状细胞病植物药物的首次临床试验

• 批准号: 8529844
• 负责人: Robert Swift
• 金额: $ 44.21万
• 依托单位: INVENUX, LLC
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8529844
• 关键词: Address; Adherence; Adult; Adverse effects; Affect; Africa; Age; Analgesics; Anemia; Animal Feed; Animals; Antineoplastic Agents; Attention; Biological Assay; Biological Markers; Blood flow; Body Weight; Bone Marrow Transplantation; Botanicals; Cell Shape; Cellular Structures; Cessation of life; Child; Chronic; Clinical Trials; Communities; County Hospitals; Coupled; Data; Developing Countries; Development; Disease; Disease Progression; Domestic Animals; Dose; Drug usage; Eating; Erythrocytes; Event; FDA approved; Folic Acid; Funding; Genes; Globin; Goals; Grant; HIV; Hematological Disease; Hemoglobin; Hereditary Disease; Human; Hyperviscosity; In Vitro; Infection; Infection prevention; Influenza vaccination; Inherited; International; Iron Overload; Learning; Left; Legal patent; Leukocytes; Liquid substance; Manuscripts; Measures; Medical; Medical Care Costs; Molecular; Morbidity - disease rate; Mus; Mutation; Neurocognitive; Oral; Organ; Organ failure; Oxygen; Pain; Pathogenesis; Penicillins; Persons; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phase I Clinical Trials; Polymers; Preparation; Procedures; Process; Property; Quality of life; Rattus; Reaction; Renal function; Research; Safety; Sickle Cell; Sickle Cell Anemia; Signs and Symptoms; Small Business Innovation Research Grant; Sorghum; Spleen; Stroke; Supportive care; Testing; Therapeutic Agents; Tissues; Toxic effect; Transfusion; Transgenic Organisms; Translating; United States; Variant; Venous blood sampling; Vulnerable Populations; base; cost; drug development; effective therapy; genotoxicity; hydroxyurea; improved; in vivo; intravenous injection; killings; meetings; mortality; mouse model; novel therapeutics; polymerization; prevent; public health relevance; response; sickling; vascular inflammation

DESCRIPTION (provided by applicant): New therapeutic agents are urgently needed for the treatment of sickle cell disease (SCD), the world's most common genetic disease. Our long-term goal is to develop a botanical drug for use in children that prevents the inexorable progression of SCD. SCD affects approximately 100,000 people in the United States and millions worldwide. It kills more children in Africa than HIV, but while HIV commands vast attention from the international community, SCD is "virtually invisible." In the US, those with SCD have an average mortality in their 40s and an estimated aggregate cost of medical care in excess of $1.4 billion per year. In less developed countries, 80% of children with SCD die before the age of five. The only FDA approved disease-modifying drug for use in SCD is the anti-cancer drug hydroxyurea, which has serious side effects and is only approved for use in adults. SCD results from a mutation in the ¿-globin gene (Hb S), a variant of Hb A, the common adult hemoglobin. When deoxygenated, Hb S polymerizes, forming long polymers that deform the biconcave red blood cells (RBCs) into rigid, adherent, sickle-shaped cells. The rigid sickled RBCs are easily trapped in the microvasculature, blocking blood flow to tissues and organs with resultant ischemic tissue damage. Best supportive therapies for SCD include folic acid for anemia, penicillin to prevent infections, pneumococcal and influenza vaccinations, pain medication, and intravenous injection of fluids. Chronic transfusion therapy can modify the course of the disease, but hyperviscosity, alloimmune reaction, infection, and iron overload are just a few of the complications of transfusion therapy. Bone marrow transplants can cure SCD, but the morbidity and mortality of the procedure, coupled with difficulty in finding a donor match and the cost of the procedure, leave this an uncommon treatment option. We propose a Phase I dose escalation trial in adults with SCD to obtain an initial safety profile and explore possible effective oral doses of a botanical drug that inhibits RBCs from sickling. The rationale for the proposed research is that inhibiting RBCs from sickling, the hallmark of the disease, will reduce anemia, reduce vasoocclusion and pain, reduce cumulative organ damage, and reduce vascular inflammation caused by the adherence of the RBCs to endothelial and white blood cells.

描述（由申请人提供）：镰状细胞病（SCD）是世界上最常见的遗传性疾病，迫切需要新的治疗药物。我们的长期目标是开发一种用于儿童的植物性药物，以防止SCD的不可阻挡的进展。SCD在美国影响约10万人，在全球影响数百万人。在非洲，死于艾滋病的儿童比死于艾滋病的儿童还多，但是，尽管艾滋病引起了国际社会的广泛关注，但SCD“实际上是看不见的”。在美国，SCD患者的平均死亡率为40多岁，每年的医疗保健总费用估计超过14亿美元。在欠发达国家，80%的SCD患儿在5岁前死亡。FDA唯一批准用于SCD的疾病改善药物是抗癌药物羟基脲，它有严重的副作用，只被批准用于成人。SCD是由血红蛋白基因（Hb S）突变引起的，这是成人常见血红蛋白Hb a的一种变体。当脱氧时，Hb S聚合，形成长聚合物，使双凹面红细胞（rbc）变形为坚硬的，粘附的，镰刀状细胞。坚硬的镰状红细胞很容易被困在微血管中，阻碍血液流向组织和器官，造成缺血性组织损伤。SCD的最佳支持疗法包括治疗贫血的叶酸、预防感染的青霉素、肺炎球菌和流感疫苗、止痛药和静脉注射液体。慢性输血治疗可以改变病程，但高粘稠度、同种免疫反应、感染和铁超载只是输血治疗的一些并发症。骨髓移植可以治愈SCD，但手术的发病率和死亡率，再加上寻找匹配供体的困难和手术的成本，使这成为一种不常见的治疗选择。我们建议在成人SCD患者中进行I期剂量递增试验，以获得初步的安全性，并探索一种抑制红细胞镰状细胞的植物性口服药物的可能有效剂量。该研究的基本原理是，抑制镰状红细胞（该病的标志）将减少贫血，减少血管闭塞和疼痛，减少累积器官损伤，并减少由红细胞粘附到内皮细胞和白细胞引起的血管炎症。