Elucidation of Antisickling Molecules in a Botanical with Antisickling Activity

具有抗镰刀活性的植物中抗镰刀分子的阐明

基本信息

批准号：
8589491
负责人：
Robert Swift
金额：
$ 39.79万
依托单位：
INVENUX, LLC
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8589491
关键词：
Address Adult Adverse effects Affect Africa Age Analgesics Anemia Antineoplastic Agents Attention Biological Assay Blood flow Bone Marrow Transplantation Botanicals Cell Shape Cessation of life Child Chronic Clinical Data Communities Coupled Data Developing Countries Development Disease Disease Progression Drug usage Erythrocytes Event FDA approved Folic Acid Fractionation Funding Genes Globin Goals Grant HIV Hematological Disease Hemoglobin Hereditary Disease Human Hyperviscosity Hypoxia In Vitro Infection Infection prevention Influenza vaccination Inherited International Iron Overload Laboratories Lead Left Legal patent Liquid Chromatography Liquid substance Manuscripts Mass Spectrum Analysis Measures Medical Medical Care Costs Molecular Morbidity - disease rate Mutation Neurocognitive Nigeria Niprisan Organ Organ failure Pain Pathogenesis Patients Penicillins Persons Pharmaceutical Preparations Phase Plant Leaves Polymers Preparation Procedures Process Property Publishing Quality of life Reaction Renal function Research Sickle Cell Sickle Cell Anemia Signs and Symptoms Small Business Innovation Research Grant Sorghum Spleen Stroke Structure Supportive care Symptoms Testing Therapeutic Agents Tissues Traditional Medicine Transfusion Transgenic Mice Transgenic Organisms United States United States National Institutes of Health Universities Variant cost drug development effective therapy hydroxyurea in vitro Assay in vivo intravenous injection killings mortality mouse model novel therapeutics polymerization prevent public health relevance scale up sickle cell crisis sickling

项目摘要

DESCRIPTION: 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 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 have identified a botanical extract with potent antisickling activity. We propose to isolate the active compounds in the botanical by bio-assay guided fractionation of the botanical extract using an in vitro assay that measures sickling of human RBCs under hypoxic conditions. The active fractions will be further fractionated, the compounds in the sub-fractions identified using mass spectroscopy and NMR, and in vivo activity confirmed in 100% human Hb S transgenic mice.

描述：迫切需要新的治疗药物来治疗镰状细胞病 (SCD)，这是世界上最常见的遗传病。我们的长期目标是开发一种用于儿童的药物，以预防 SCD 影响的不可避免的进展。在美国，它导致大约 100,000 人死亡，在全世界则有数以百万计的儿童死亡，但尽管艾滋病毒引起了国际社会的广泛关注，但 SCD 在非洲却“几乎看不见”。在美国，SCD 患者的平均死亡率为 40 多岁，每年医疗费用估计超过 14 亿美元。在欠发达国家，80% 的 SCD 儿童在五岁之前死亡。用于治疗 SCD 的疾病缓解药物是抗癌药物羟基脲，它具有严重的副作用，并且仅被批准用于由 ¿ 突变引起的 SCD。 -球蛋白基因 (Hb S)，Hb A（常见的成人血红蛋白）的一种变体。当脱氧时，Hb S 会聚合，形成长聚合物，使双凹红细胞 (RBC) 变形为坚硬、粘附的镰状细胞。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，从而导致缺血性组织损伤。 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治疗可以改变病程，但高粘滞血症、同种免疫反应、感染和铁超负荷只是输血并发症的一小部分。骨髓移植可以治愈 SCD，但该手术的发病率和死亡率，加上寻找匹配捐献者的难度和手术费用，使得这种治疗方法并不常见。我们已经确定了一种具有有效抗镰状化活性的植物提取物，我们建议通过生物测定引导的植物提取物分级分离，使用体外测定来测量缺氧条件下人类红细胞的镰状化。进一步分级，使用质谱和 NMR 鉴定亚级分中的化合物，并在 100% 人 Hb S 转基因小鼠中确认体内活性。