Targeting PGC-1a for the treatment of sickle cell disease

摘要 镰状细胞病（SCD）和β-地中海贫血是影响结构或生产的遗传性疾病， 血红蛋白。它们正在增加全球健康负担，困扰着世界各地数百万人。胎儿充足 血红蛋白（HbF）诱导可以降低SCD的发病率和死亡率。β-地中海贫血也是如此。的 在成人中，SCD羟基脲（HU）中HbF诱导的标准现行治疗通常不会改善 足够的镰状血管闭塞或溶血。因此，寻求更有效、更安全的小型 分子HbF诱导剂是SCD管理中关键的未满足的需求。我们最近发现， 过氧化物酶体增殖物激活受体γ共激活因子-1（PGC-1 β）参与了 珠蛋白基因慢病毒感染或小分子化合物ZLN 005上调人PGC-1α表达 原代红系祖细胞CD 34+细胞诱导HbF表达，并增加F细胞的百分比， 影响细胞增殖和分化。ZLN 005对PGC-1α的激活可能为PGC-1α的表达提供了新的途径。 血红蛋白调节在SCD中具有有希望的治疗益处。我们打算测试体内治疗 ZLN 005在镰状细胞小鼠中的作用。这些临床前研究的结果可以提供初步证据， 开发更安全，更有益的小分子治疗SCD治疗的原则，并导致早期 阶段临床试验。

ABSTRACT Sickle cell disease (SCD) and -thalassemia are genetic disorders affecting the structure or production of hemoglobin. They are growing global health burden afflicting millions around the world. Sufficient fetal hemoglobin (HbF) induction can reduce morbidity and mortality in SCD. The same is true for -thalassemia. The standard current therapy for HbF induction in SCD hydroxyurea (HU) which in adults, does not usually ameliorate sufficiently either sickle vaso-occlusion or hemolysis. Therefore, the search for more effective and safer small molecule HbF inducers is a key unmet need in the management of SCD. We recently discovered that the peroxisome proliferator activated receptor gamma coactivator-1 (PGC-1) is involved in the regulation of the globin genes. Upregulation of PGC-1α by lentivirus infection or by a small molecule compound ZLN005 in human primary erythroid progenitor CD34+ cells induced HbF expression and increased the percent of F-cells without affecting cell proliferation and differentiation. Activation of PGC-1α by ZLN005 might provide a new path into hemoglobin regulation with a promising therapeutic benefit in SCD. We intend to test for in vivo therapeutic effects of ZLN005 in sickle cell mice. The findings from these preclinical studies could provide initial proof of principle for developing safer, more beneficial small molecule therapeutics for SCD treatment and lead to early- phase clinical trials.