Development of tools to modify globin gene expression in stem cells

开发修改干细胞中球蛋白基因表达的工具

• 批准号: 8058307
• 负责人: LLOYD G MITCHELL
• 金额: $ 52.13万
• 依托单位: RETROTHERAPY, LLC
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-20 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8058307
• 关键词: Autologous; Back; Biological Models; Bone Marrow; Bone Marrow Stem Cell; CD34 gene; Cells; Chronic Granulomatous Disease; Clinical Protocols; Collecting Cell; Complementary DNA; Development; Disease; Ectopic Expression; Equilibrium; Erythrocytes; Fetal Hemoglobin; Fluorescence-Activated Cell Sorting; Gene Expression; Genes; Globin; Goals; Hematopoietic stem cells; Hemoglobin; Hemoglobinopathies; Hereditary Disease; Human; Investigation; Kidney; Laboratories; Lead; Length; Libraries; Life; Life Expectancy; Liver; Lung; Mediating; Messenger RNA; Modeling; Organ; Other Genetics; Pain; Patients; Phase; Plasmids; Proteins; RNA; Reporting; Research Personnel; Sickle Cell Anemia; Specificity; Spleen; Spliceosomes; Staging; Stem cells; Stroke; Symptoms; Techniques; Technology; Testing; Thalassemia; Therapeutic; Time; Tissues; Trans-Splicing; Transcript; Transgenes; United States National Institutes of Health; base; beta Globin; expression vector; fetal; gene correction; gene therapy; improved; in vivo Model; mRNA Precursor; method development; mutant; novel therapeutic intervention; pre-clinical; prevent; protein expression; sickling; therapeutic protein; therapeutic transgene; tool development; transgene expression; vector

DESCRIPTION (provided by applicant): Development of tools to modify globin gene expression in stem cells The objective of this proposal is to develop a treatment for patients with sickle cell disease. The development of methods for treating common genetic diseases, such as sickle cell disease remains an elusive goal. Gene therapy is a technology which has the potential to overcome several of the problems in the development of a therapy for sickle cell disease. Hemoglobinopathies offer a major advantage for researchers in that their stem cells reside in the bone marrow. They are easy to access, manipulate in the laboratory and can be given back to the patient. This proposal intends to create optimized gene expression vectors that reduce mutant sickle beta-globin protein levels while increasing the expression of another normal globin gene, thus maintaining the balance of hemoglobin protein expression that is critical to the formation of normal red blood cells. These vectors will be tested in human bone marrow stem cells to determine their potential to improve hemoglobin expression. PUBLIC HEALTH RELEVANCE: Patients with Sickle Cell Disease suffer from a range of many symptoms including painful sickle crises, damage to organs such as the lungs, kidneys, liver and spleen and stroke, which shorten life expectancy to the mid-40's. At present there is no curative treatment for majority of patients with this common genetic disease. Although there are a number of possible treatments currently under investigation which may reduce the disease complications or offer the potential of a cure, this proposal seeks to develop a new therapeutic approach that has demonstrated potential in models of other genetic diseases.

描述（由申请人提供）：开发修改干细胞中球蛋白基因表达的工具该提案的目的是开发针对镰状细胞病患者的治疗方法。开发治疗镰状细胞病等常见遗传病的方法仍然是一个难以实现的目标。基因疗法是一种有潜力克服镰状细胞病疗法开发中的几个问题的技术。血红蛋白病为研究人员提供了一个主要优势，因为它们的干细胞存在于骨髓中。它们易于在实验室中获取和操作，并且可以返回给患者。该提案旨在创建优化的基因表达载体，降低突变镰状β珠蛋白水平，同时增加另一个正常珠蛋白基因的表达，从而维持对正常红细胞形成至关重要的血红蛋白表达的平衡。这些载体将在人类骨髓干细胞中进行测试，以确定它们改善血红蛋白表达的潜力。 公众健康相关性：镰状细胞病患者会出现一系列症状，包括痛苦的镰状细胞危象、肺、肾、肝、脾等器官受损以及中风，这些症状会使预期寿命缩短至 40 多岁。目前，大多数患有这种常见遗传病的患者还没有有效的治疗方法。尽管目前正在研究许多可能的治疗方法，这些治疗方法可能会减少疾病并发症或提供治愈的潜力，但该提案旨在开发一种新的治疗方法，该方法已在其他遗传疾病模型中显示出潜力。

项目成果

RNA Trans-Splicing Targeting Endogenous β-Globin Pre-Messenger RNA in Human Erythroid Cells.

RNA 反式剪接靶向人红细胞中的内源性β-珠蛋白前信使 RNA。

• DOI: 10.1089/hgtb.2016.077
• 发表时间: 2017
• 期刊: Human gene therapy methods
• 作者: Uchida,Naoya;Washington,KareemN;Mozer,Brian;Platner,Charlotte;Ballantine,Josiah;Skala,LukeP;Raines,Lydia;Shvygin,Anna;Hsieh,MatthewM;Mitchell,LloydG;Tisdale,JohnF
• 通讯作者: Tisdale,JohnF