Development of tools to modify globin gene expression in stem cells

描述（由申请人提供）：开发修饰干细胞中珠蛋白基因表达的工具本提案的目的是开发镰状细胞病患者的治疗方法。开发用于治疗常见遗传性疾病如镰状细胞病的方法仍然是一个难以实现的目标。基因治疗是一种有潜力克服镰状细胞病治疗发展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，因为他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，并可以返回给患者。该提案旨在创建优化的基因表达载体，其降低突变型镰状β-珠蛋白蛋白水平，同时增加另一种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蛋白表达的平衡。这些载体将在人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。 公共卫生相关性：镰状细胞病患者会出现一系列症状，包括疼痛的镰状危象，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没有治愈性治疗方法。虽然目前正在研究一些可能的治疗方法，可以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表现出潜力。

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.