Elucidation of Antisickling Molecules in a Botanical with Antisickling Activity

描述：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药物，以防止SCD的不可阻挡的进展。SCD影响美国约100，000人和全球数百万人。它在非洲杀死的儿童比艾滋病毒更多，但尽管艾滋病毒引起了国际社会的广泛关注，SCD“几乎是看不见的”。“在美国，SCD患者的平均死亡率为40多岁，估计每年的医疗保健总成本超过14亿美元。在欠发达国家，80%的SCD儿童在5岁之前死亡。FDA批准的唯一用于SCD的疾病修饰药物是抗癌药物羟基脲，它具有严重的副作用，仅被批准用于成人。 SCD是由<$-珠蛋白基因（Hb S）突变引起的，Hb S是常见的成人血红蛋白Hb A的变体。当脱氧时，Hb S聚合，形成长的聚合物，使双凹面红细胞（RBC）变形为刚性的、粘附的、镰刀形的细胞。刚性镰状红细胞很容易被困在微血管系统中，阻断血液流向组织和器官，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的少数并发症。骨髓移植可以治愈SCD，但该手术的发病率和死亡率，加上难以找到供体匹配和手术费用，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枯萎活性的植物提取物。我们建议通过生物测定指导的植物提取物的分级分离植物中的活性化合物，使用在缺氧条件下测量人RBC镰状化的体外测定。将进一步分离活性组分，使用质谱和NMR鉴定亚组分中的化合物，并在100%人Hb S转基因小鼠中确认体内活性。

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.