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

• 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
• 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

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： 镰状细胞病（SCD）是世界上最常见的遗传病，迫切需要新的治疗药物来治疗。我们的长期目标是开发一种用于儿童的药物，预防 SCD 的不可避免的进展。 SCD 影响着美国约 100,000 人以及全世界数百万人。它在非洲杀死的儿童比艾滋病毒还要多，但尽管艾滋病毒引起了国际社会的广泛关注，但性猝死“几乎是看不见的”。在美国，SCD 患者的平均死亡率为 40 多岁，估计每年的医疗费用总额超过 14 亿美元。在欠发达国家，80% 的 SCD 儿童在五岁之前死亡。 FDA 唯一批准用于治疗 SCD 的疾病缓解药物是抗癌药物羟基脲，该药物具有严重的副作用，并且仅被批准用于成人。 SCD 是由 ¿-球蛋白基因 (Hb S) 突变引起的，该基因是常见成人血红蛋白 Hb A 的变体。脱氧时，Hb S 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。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，从而导致缺血性组织损伤。 SCD 的最佳支持疗法包括叶酸治疗贫血、青霉素预防感染、肺炎球菌和流感疫苗接种、止痛药和静脉注射液体。慢性输血治疗可以改变病程，但高粘血症、同种免疫反应、感染和铁超负荷只是输血治疗并发症的一小部分。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，使其成为一种不常见的治疗选择。 我们已经鉴定出一种具有有效抗镰刀活性的植物提取物。我们建议通过生物测定引导的植物提取物分级分离，使用体外测定来分离植物中的活性化合物，该体外测定测量缺氧条件下人类红细胞的镰状化。活性组分将被进一步分级，使用质谱和核磁共振鉴定子组分中的化合物，并在 100% 人 Hb S 转基因小鼠中确认体内活性。