Development of a Clinical Hemoglobin Modulator

β-地中海贫血和血红蛋白病是严重的遗传性血液疾病，它们是 世卫组织--被指定为日益沉重的全球卫生负担。这些疾病会减少产量或改变 成人血红蛋白A的β链的结构，并引起溶血性贫血，慢性器官 损害和早期死亡率。胎儿珠蛋白(HBF)是另一种正常的血红蛋白，它是 在胎儿发育过程中表达，但在婴儿时期被抑制。几十年的研究表明 HbF的任何增量增加都会降低镰状细胞病和β的严重程度- 地中海贫血。药物促进胎儿血红蛋白(γ-珠蛋白链)的产生 被接受为减少潜在病理的一种治疗方式。我们用了高价- 对EMA或FDA目前批准的用于其他药物的药物库进行吞吐量筛选 医疗条件，确定了一小组以前未被承认的药物，这些药物导致 胎儿珠蛋白基因，并在患者的非人类红血球祖细胞中验证其作用 灵长类动物和转基因小鼠。一种治疗方法，苯丝肼，诱导胎儿珠蛋白增加30倍 超过基线，间歇性口服治疗贫血的狒狒，并被发现废除， 抑制或取代胎儿基因启动子BCL11A的4个有效分子抑制子， LSD-1、KLF-1和HDAC3，导致“化学基因编辑”。 在欧洲和加拿大，苯丝肼作为一种氨基酸脱羧酶已经使用了40年。 抑制剂，以提高另一种有效成分的pk治疗复方片剂 帕金森氏症，具有良性的安全性，在慢性剂量至 每天1300毫克。这项提案将评估贝色拉齐特的人体等量剂量。 从贫血狒狒和转基因小鼠的主动剂量推断，为了耐受性， 24例β地中海贫血患者的药代动力学和胎儿珠蛋白表达分析 中间媒体和多达12名镰状细胞疾病患者。 目标包括： 目的I：评价3种剂量的苯丝肼治疗24例β地中海贫血的耐受性和PK 中间媒体(BTI)患者，在3个剂量递增队列和1个扩展队列中治疗12人 周数 目的II：初步研究苯丝肼诱导16BTI细胞HbF表达的活性 患者，以及一组镰状细胞病患者，与基线相比在以下方面发生了变化： 亚拉。网织红细胞、F细胞、MFI、HbF、总血红蛋白和红细胞压积 IIB。溶血标志物(STfr、LDH、胆红素)测定 这项研究应该为进行确定的PH2或3的分子临床试验提供基础。 针对这两种全球性血液疾病的靶向治疗。

The β-thalassemias and hemoglobinopathies are serious genetic blood diseases, which are WHO-designated as a growing global health burden. The disorders decrease production or alter the structure of the β-chain of adult hemoglobin A, and cause hemolytic anemia, chronic organ damage, and early mortality. Fetal globin (HbF) is another type of normal hemoglobin, which is expressed during fetal development but suppressed in infancy. Decades of research have shown that any incremental increase in HbF reduces the severity of sickle cell disease and β- thalassemia. Pharmacologic augmentation of fetal hemoglobin (γ-globin chain) production, is accepted as one therapeutic modality to reduce the underlying pathology. We applied high- throughput screening to study a library of drugs currently approved by the EMA or FDA for other medical conditions, identified a small panel of previously unrecognized drugs which induce the fetal globin gene, and validated their action in patients’ red blood cell progenitors, nonhuman primates, and transgenic mice. One therapeutic, Benserazide, induced fetal globin up to 30-fold over baseline with intermittent oral treatment in anemic baboons, and was found to abolish, suppress, or displace 4 potent molecular repressors of the fetal gene promoter, BCL11A, LSD-1, KLF-1, and HDAC3, causing “chemical gene editing”. Benserazide has been used for 4 decades in Europe and Canada as an amino acid decarboxylase inhibitor, to enhance the PK of another active agent in a combination tablet for treatment of Parkinson’s disease, has a benign safety profile and is considered safe at chronic doses up to 1300 mg per day. This proposal will evaluate Benserazide at human equivalent doses extrapolated from active dosing in anemic baboons and transgenic mice, for tolerability, pharmacokinetics, and fetal globin expression assays in up to 24 patients with beta thalassemia intermedia and up to 12 patients with sickle cell disease. The Aims include: Aim I: To evaluate tolerability and PK of 3 doses of Benserazide in 24 beta thalassemia intermedia (BTI) patients, in 3 dose-escalating cohorts and an expansion cohort treated for 12 weeks Aim II: To investigate preliminary activity of Benserazide in inducing HbF expression in up to 16 BTI patients, and in one cohort of patients with sickle cell disease, as change from baseline in: IIa. F-reticulocytes, F-cells, MFI, HbF, total hemoglobin and hematocrit IIb. Assays of markers of hemolysis (STfr, LDH, bilirubin) The study should provide a basis for conducting definitive Ph2 or 3 clinical trials of a molecularly targeted therapy for these two global blood disorders.