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：迫切需要新的治疗剂来治疗世界上最常见的遗传疾病（SCD）。我们的长期目标是开发一种药物供儿童使用，以防止SCD的不可阻碍。 SCD影响着美国约100,000人，在全球范围内影响数百万。它杀死了非洲比艾滋病毒更多的儿童，但是尽管艾滋病毒引起了国际社会的广泛关注，但SCD“几乎看不见”。在美国，患有SCD的人在40多岁时平均死亡率，估计每年超过14亿美元的医疗服务总成本。在不太发达国家，有80％的SCD儿童在五岁之前死亡。唯一可以在SCD中使用的FDA批准的疾病改良药物是抗癌药物羟基脲，该药物具有严重的副作用，仅批准用于成人。 SCD是由€globin基因（HB S）的突变引起的，这是HB A的变体，常见的成年血红蛋白。当脱氧时，HB S会聚合，形成长聚合物，使双孔红细胞（RBC）变形为刚性，坚固，镰状细胞。刚性镰刀式的RBC很容易被困在微脉管系统中，阻塞了组织和器官的血液流动，导致缺血组织损伤。 SCD的最佳支撑疗法包括用于贫血的叶酸，预防感染的青霉素，肺炎球菌和影响者疫苗接种，止痛药以及液体静脉注射。慢性输血疗法可以改变疾病的病程，但是高管性，同种免疫反应，感染和铁超负荷只是输血疗法的一些并发症。骨髓移植可以治愈SCD，但是该手术的发病率和死亡率，再加上很难找到供体匹配和手术成本，这是一个罕见的治疗选择。我们已经鉴定出具有潜在抗精性活性的植物提取物。我们建议使用在低氧条件下测量人类RBC的生物测定法分离植物提取物中的植物性化合物。活性级分将进一步分馏，使用质谱和NMR鉴定的亚裂缝中的化合物，在100％人类HB S转基因小鼠中证实了体内活性。