Development of a clinical hemoglobin modulator

描述（由申请人提供）：地中海贫血和镰状细胞病是严重的遗传性血液疾病，被世卫组织指定为日益增长的全球卫生负担。这些疾病减少成人血红蛋白A b链的产生或改变其结构，其特征是贫血、慢性器官损伤和早期死亡。HbF是另一种在婴儿期被抑制的正常血红蛋白。数十年的研究表明，HbF的任何增加都会降低镰状细胞病和威胁生命的b-地中海贫血的严重程度。药物增加胎儿血红蛋白（g-球蛋白链）的产生，以取代有缺陷或缺失的b-球蛋白链，被认为是一种治疗方式。只有一种治疗药物羟基脲被批准用于治疗镰状细胞病，没有明确的治疗药物被批准用于治疗地中海贫血。需要额外的HbF诱导疗法。我们使用了一种新的高通量筛选程序来询问已经获得EMEA或fda批准用于其他医疗条件的药物库，并确定了一组以前未被识别的强效hbf诱导药物。在患者的红系祖细胞中，二级报告基因试验验证了hbf诱导活性，并且在我们的I期str资助下，在狒狒中评估了3种先导疗法。这种灵长类动物模型可以预测人类对其他药物的反应。在狒狒中，一种名为Benserazide的治疗药物在诱导高水平的胎儿珠蛋白方面特别引人注目，比基线高出33倍。我们发现该药物抑制胎儿血红蛋白基因主要抑制复合物的两个组分。该药在欧洲和加拿大作为左旋多巴的PK增强剂用于治疗帕金森病已有30年的历史，并且具有良好的安全性。因此，我们建议将苯塞拉肼重新用于治疗β血红蛋白病。我们的目标包括：目标一：确定Benserazide的最佳给药方案，用于在贫血非人灵长类动物体内诱导持续HbF；目标二：生产适合血红蛋白病患者剂量范围试验的配方；目标三：获得美国IND，以评估欧盟批准的镰状细胞病和地中海贫血患者的治疗

DESCRIPTION (provided by applicant): The ¿-thalassemias and sickle cell disease are serious genetic blood diseases, which are WHO- designated as a growing global health burden. The disorders decrease production or alter structure of the b-chain of adult hemoglobin A and are characterized by anemia, chronic organ damage, and early mortality. HbF is another type of normal hemoglobin which is suppressed in infancy. Decades of research have shown that any incremental increase in HbF reduces the severity of sickle cell disease and the life-threatening anemia of b-thalassemia. Pharmacologic augmentation of fetal hemoglobin (g-globin chain) production, to replace the defective or missing b-globin chains, is accepted as a therapeutic modality. Only one therapeutic, hydroxyurea, is approved for sickle cell disease, and no definitive therapeutic agent is approved for beta thalassemia. Additional HbF- inducing therapies are needed. We utilized a novel high-throughput screening program to interrogate a library of drugs which are already EMEA or FDA-approved for other medical conditions, and identified a panel of previously unrecognized potent HbF-inducing drugs. HbF-inducing activity was validated in a secondary reporter assays, in patients' erythroid progenitors, and 3 lead therapeutics were evaluated in baboons on our Phase I STTR grant. This primate model has been predictive of subsequent human responses for other drugs. One therapeutic, Benserazide, was particularly intriguing in inducing high-level fetal globin, by 33-fold over baseline, with brif treatment in the baboon. We found the drug suppresses two components of a major repressor complex of the fetal hemoglobin gene. The drug has been used for 3 decades in Europe and Canada as a PK enhancer of levodopa for treatment of Parkinson's disease, and has a benign safety profile. Accordingly, we propose to repurpose Benserazide for treatment the beta hemoglobinopathies. Our Aims include: Aim I: Determine an optimal dosing regimen of Benserazide for inducing sustained HbF in vivo in anemic nonhuman primates Aim II: Produce a formulation suitable for a dose-ranging trial in hemoglobinopathy patients Aim III: Obtain a US IND to evaluate the EU-approved therapeutic in patients with sickle cell disease and beta thalassemia