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

 描述(申请人提供)：世界上最常见的遗传病--镰状细胞病的治疗急需新的治疗剂。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)，以减缓或阻止疾病的进展。镰状细胞病影响着美国约10万人和全球数百万人。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5岁之前死亡。FDA批准的唯一用于SCD的疾病修正药物是抗癌药物羟基脲，该药物具有严重的副作用，仅被批准用于成人。镰状细胞病是由于β-珠蛋白基因(Hb S)的突变引起的，Hb A是成人常见的血红蛋白。当脱氧时，血红蛋白S聚合，形成长聚合物，使双凹红细胞(RBC)变形为坚硬的、粘连的镰刀状细胞。坚硬的镰状红细胞很容易被困在微血管中，阻止流向组织和器官的血液，从而导致组织缺血损伤。对SCD最好的支持性治疗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接种、止痛药和静脉注射液体。慢性输血疗法可以改变疾病的进程，但高粘滞性、同种异体免疫反应、感染和铁超载只是输血疗法的几个并发症。骨髓移植可以治愈SCD，但该手术的发病率和死亡率，再加上难以找到匹配的捐赠者和手术费用，使其成为一种不常见的治疗选择。SCD-101正在成人镰状细胞疾病的1B期剂量递增试验中进行评估，以获得初步的安全性概况并探索 可能有效的口服剂量，以抑制红细胞的镰状。早期数据显示，SCD-101可以抑制人类的红细胞病态。要进入第二阶段临床试验，还需要进行额外的非临床研究。这项第二阶段拨款建议是为必要的非临床研究提供资金。

 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.