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

靶向 PGC-1a 治疗镰状细胞病

• 批准号: 10641009
• 负责人: Shuaiying Cui
• 金额: $ 35万
• 依托单位: BOSTON MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10641009
• 关键词: Adenovirus Infections; Adult; Adverse effects; Affect; Agonist; Anemia; Binding; Biogenesis; Birth; Blood; Bone Marrow Cells; CD34 gene; Cell Differentiation process; Cell Proliferation; Cells; Characteristics; Clinical; Clinical Research; DNA Binding Domain; Data; Development; Disease; Embryo; Erythrocytes; Erythroid; Erythroid Cells; Erythroid Progenitor Cells; Erythropoiesis; Fetal Hemoglobin; Fetus; Functional disorder; Gene Expression; Genes; Genetic Diseases; Genetic Transcription; Globin; Hematology; Hemoglobin; Hemoglobin A; Hemoglobin concentration result; Hemolysis; Hemolytic Anemia; Hereditary Disease; Histologic; Homologous Gene; Human; In Vitro; Knockout Mice; Laboratory Study; Lentivirus Infections; Life; Link; Messenger RNA; Methods; Missense Mutation; Mitochondria; Modeling; Molecular; Molecular Target; Morbidity - disease rate; Mus; Organ; PPAR gamma; Pathology; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Polymers; Population; Preclinical Testing; Production; Regulation; Regulator Genes; Repressor Proteins; Research; Severity of illness; Sickle Cell; Sickle Cell Anemia; Sickle Hemoglobin; Structure; Thalassemia; Therapeutic; Therapeutic Effect; Up-Regulation; beta Thalassemia; early phase clinical trial; epsilon Globin; gamma Globin; gene therapy; global health; heme biosynthesis; hemoglobin polymer; hydroxyurea; in utero; in vivo; in vivo evaluation; induced pluripotent stem cell; iron metabolism; loss of function; man; mortality; mouse model; novel; overexpression; pharmacologic; polymerization; preclinical study; prenatal therapy; prevent; progenitor; promoter; receptor; sickle vasoocclusion; sickling; small molecule; small molecule therapeutics; standard of care; transcription factor

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.

摘要 镰状细胞病和-地中海贫血是影响结构或生产的遗传性疾病 血红蛋白的含量。它们正在增加全球健康负担，困扰着世界各地的数百万人。足量胎儿 诱导血红蛋白(HBF)可降低SCD的发病率和死亡率。-地中海贫血也是如此。这个 标准电流疗法在成人SCD羟基尿素(HU)中诱导HBF通常不会改善 足够的镰刀状血管闭塞或溶血。因此，寻找更有效、更安全的小 分子HBF诱导剂是SCD治疗中尚未满足的关键需求。我们最近发现， 过氧化物酶体增殖物激活受体γ辅活化子-1(pGC-1)参与细胞周期调控。 珠蛋白基因。慢病毒感染和小分子化合物ZLN005对人PGC-1α的上调作用 原代红系祖细胞CD34+细胞诱导HBF表达并增加F-细胞百分率 影响细胞增殖和分化的。ZLN005激活pGC-1α可能为进入 血红蛋白调节在SCD中有很好的治疗效果。我们打算测试体内的治疗方法 ZLN005对镰状细胞小鼠的影响。这些临床前研究的发现可以提供初步的证据 为治疗SCD开发更安全、更有益的小分子疗法并导致早期... 阶段临床试验。