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

靶向 PGC-1a 治疗镰状细胞病

基本信息

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
项目类别：
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

项目摘要

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（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。