Novel Gene Editing Approaches for Hemoglobinopathies

治疗血红蛋白病的新基因编辑方法

基本信息

批准号：
9261866
负责人：
HANS-PETER KIEM
金额：
$ 95.98万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-01-17 至 2020-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9261866
关键词：
Acute Address Affect Africa Allogenic Animal Model Animals Architecture Autologous Blood Cells CD34 gene Cardiopulmonary Cell Transplantation Cells Cellular biology Child Childhood Clinic Clinical Collaborations Cooley&apos s anemia DNA Double Strand Break DNA cassette Data Set Development Disease Dose Economics Effectiveness Engineering Engraftment Erythroid Erythropoiesis Evaluation Foundations Gene Targeting Gene-Modified Generations Genes Genetic Recombination Genome Globin Goals Graft Rejection Healthcare Hematological Disease Hematopoiesis Hematopoietic stem cells Hemoglobin Hemoglobin F Disease Hemoglobinopathies Hospitalization Human Immunologics In Situ Inborn Genetic Diseases Infection Infusion procedures Kidney Long-Term Care Longevity MGMT gene Macaca Maintenance Methods Modeling Modernization Modification Organ Organism Patients Phase Positioning Attribute Procedures Production Protocols documentation Publishing Quality of life Regimen Research Personnel Series Sickle Cell Anemia Site Specificity Stem cell transplant Stem cells Stroke Technology Testing Therapeutic Therapeutic procedure Toxic effect Translations Transplantation Treatment Efficacy Work Xenograft Model base beta Globin beta Thalassemia chronic pain clinical efficacy clinically relevant conditioning cost design gamma Globin gene replacement gene replacement therapy gene therapy global health health economics human morbidity improved in vivo method development nonhuman primate novel nuclease pre-clinical promoter reconstitution research clinical testing stem therapeutic gene translational approach vector

项目摘要

Disorders of hemoglobin production are the most common inherited disorders of hematopoiesis, and are a cause of immense human morbidity and economic loss across the globe. Recent advances in gene-editing technology have demonstrated the potential to directly manipulate the endogenous globin locus in human hematopoietic stem and progenitor cells. However, significant barriers remain for translation of gene editing as an effective therapeutic approach to disorders of globin production, including 1) definition of gene-edited globin locus architectures that support high levels of non-sickling globin production, 2) maintenance of multi-lineage reconstitution capability of gene-edited HSPC, and 3) development of methods for efficient engraftment and selection of gene-edited HPSC. In this application, we propose two coordinated specific aims that collectively address these barriers. Specific Aim 1 will utilize recently published methods for efficient HSPC gene editing to define globin locus architecture(s) that support high levels of erythroid specific globin production and that enable post-engraftment selection of gene-edited cells. Specific Aim 2 will evaluate engraftment and selection protocols for gene-edited HSPC in a clinically relevant macaque autologous transplant model. Collectively, the proposed studies will define an optimized globin gene editing procedure along with a IND-enabling pre-clinical data set that will serve as a foundation for translation of therapeutic gene editing for disorders of β-globin synthesis to phase I clinical testing in humans.

血红蛋白产生的疾病是造血的最常见遗传疾病，是一种全球巨大的人类发病率和经济损失的原因。基因编辑的最新进展技术已经证明了直接操纵人内源性球蛋白基因座的潜力造血干和祖细胞。但是，仍然存在重大障碍，以翻译基因编辑为环球蛋白产生疾病的有效治疗方法，包括1）基因编辑的环球蛋白的定义支持高水平的非助攻球蛋白生产的基因座体系结构，2）维护多部件基因编辑的HSPC的重建能力，以及3）开发有效植入和的方法基因编辑的HPSC的选择。在此应用程序中，我们提出了两个协调的特定目标解决这些障碍。具体目标1将利用最近发表的方法进行有效的HSPC基因编辑定义球蛋白基因座架构，该体系结构支持高水平的红斑特异性球蛋白产生，并且启用基因编辑细胞的过渡后选择。特定目标2将评估植入和选择基因编辑的HSPC方案在临床相关的猕猴自体移植模型中。集体，拟议的研究将定义一个优化的球蛋白基因编辑程序，以及临时临床前将作为β-珠蛋白疾病的理论基因编辑转换基础的数据集与人类I期临床测试合成。