Safety Studies for Clinical Trials of a Botanical Drug for Sickle Cell Disease

 描述（由申请人提供）：镰状细胞病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和成人的植物药物（SCD- 101），减缓或阻止疾病进展。镰状细胞病影响美国约10万人和全世界数百万人。在美国，SCD患者的平均死亡率在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。 镰状细胞病是由β-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。 SCD-101正在镰状细胞病成人中进行1B期剂量递增试验，以获得初步安全性特征，并探索 可能有效的口服剂量，抑制红细胞镰状化。早期数据显示，SCD-101可以抑制人体RBC镰状化。为了进行II期临床试验，需要进行额外的非临床研究。第二阶段的拨款建议是资助必要的非临床研究。

 DESCRIPTION (provided by applicant): New therapeutic agents are urgently needed for the treatment of sickle cell disease, the world's most common genetic disease. Our long-term goal is to develop a botanical drug (SCD- 101) for use in children and adults that slows or stops disease progression. Sickle cell disease affects approximately 100,000 people in the United States and millions worldwide. 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. Sickle cell disease results from a mutation in the β-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. SCD-101 is being evaluated in a Phase 1B dose escalation trial in adults with sickle cell disease to obtain an initial safety profile and explore possible effective oral doses that inhibit RBCs from sickling. Early data shows that SCD-101 can inhibit RBC sickling in humans. To proceed to a Phase II clinical trial additional non-clinical studies are needed. This Phase II grant proposal is for funding the necessary non-clinical studies.