Stem Cell Gene Therapy for Hemaglobinopatathies

血红蛋白病的干细胞基因疗法

• 批准号: 7275412
• 负责人: George Stamatoyannopoulos
• 金额: $ 31.7万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7275412
• 关键词: Adenoviridae; Lentivirus; Retroviridae; adeno associated virus group; biotechnology; bone marrow transplantation; gene delivery system; gene expression; gene therapy; genetic promoter element; genetic regulatory element; genetic transduction; genetically modified animals; globin; hematopoietic stem cells; hemoglobinopathy; hemoprotein structure; laboratory mouse; nucleic acid sequence; recombinant virus; therapy adverse effect; therapy design /development; transcription factor; transfection /expression vector; virus integration

In order for gene therapy of the hemoglobinopathies to become a reality, gene transfer must be developed that are capable of high-level expression, that can efficiently transduce hematopoietic stem cells, and do not cause disease. The goal of this project is to perform studies relevant to these three challenges. Specific Aim 1 is directed toward our continued investigations of chromatin insulators, elements that can increase both the expression and possibly the safety of gene transfer vectors. This includes testing the activity of a prototypic insulator in a primate transplantation model, and cloning and characterizing new chromatin insulators. Specific Aim 2 is directed toward characterizing new chromatin insulators. Specific Aim 2 is directed toward characterizing the sites of vector integration in clinically, relevant hematopoietic cells, with a special emphasis on identifying any preference for open chromatin, a unique chromosomal structure associated with active genes. Specific Aim 3 is directed toward characterizing the properties of virus vectors for globin gene available now and to be developed by the Program Project participants, in a clinically relevant primate transplantation model. This includes vectors base on a variety of recombinant viruses such as oncoretroviruses, lentiviruses, foamy viruses, and hybrid adeno / adeno-associated viruses. Combined with the other Projects of this Program Project, these specific aims will improve both the safety and efficacy of recombinant virus vectors for globin genes, and provide critical insights into the potential risks and benefits of these vectors prior to their use in clinical trials.

为了使血红蛋白病的基因治疗成为现实，必须开发出能够有效表达高级表达的基因转移，可以有效地转导造血干细胞并不会引起疾病。该项目的目的是进行与这三个挑战有关的研究。具体目标1是针对我们对染色质绝缘子的持续研究，这些元素可以增加表达，甚至可能增加基因转移载体的安全性。这包括在灵长类动物移植模型中测试原型绝缘子的活性，以及​​克隆和表征新的染色质绝缘子。特定的目标2针对表征新的染色质绝缘子。特定的目标2用于表征临床上相关造血细胞中向量整合的位点，并特别强调识别对开放染色质的任何偏爱，这是一种与活性基因相关的独特染色体结构。特定的目标3旨在表征现已可用的Globin基因的病毒向量的特性，并在计划项目参与者中开发的Globin基因，并在临床上相关的灵长类动物移植模型中开发。这包括基于各种重组病毒的载体，例如癌症病毒，慢病毒，泡沫病毒和杂种腺 /腺相关病毒。结合该计划项目的其他项目，这些特定目标将提高重组病毒载体对球蛋白基因的安全性和功效，并在临床试验中使用这些媒介之前对这些向量的潜在风险和益处提供关键见解。