Improving transfusion therapy for patients with sickle cell disease with pluripotent stem cell-derived red cells

使用多能干细胞衍生的红细胞改善镰状细胞病患者的输血治疗

基本信息

批准号：
9353457
负责人：
STELLA T CHOU
金额：
$ 96.94万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-15 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9353457
关键词：
Ablation Address Adult African African American Alloimmunization Antibodies Antibody Formation Antibody Specificity Antigens Area Biological Assay Blood Blood Banks Blood Group Antigens Blood donor Bone Marrow CRISPR/Cas technology Caring Cell Differentiation process Cell Line Cell surface Cells Chronic Clinical Complex Complication Custom Data Development Donor Selection Erythroblasts Erythrocyte Transfusion Erythrocytes Erythroid Erythroid Cells European Evaluation Exhibits Fetal Liver Frequencies Future GATA1 gene Gene Expression Genes Genetic Variation Genotype Globin Goals Grant Hematopoiesis High Prevalence Human In Vitro Incidence Individual Knock-out Laboratories Life Measures Megakaryocytes Methods Morbidity - disease rate Morphology Mus Outcome Patients Performance Phenotype Pluripotent Stem Cells Production Protocols documentation Reagent Research Personnel Safety Savings Serum Sickle Cell Anemia Source Standardization Stem cells Stroke prevention Stromal Cells Surface Antigens TP53 gene Techniques Technology Testing Therapeutic Transfusion Variant Yolk Sac base cost design fetal genetic variant genetically modified cells genome editing genome-wide human pluripotent stem cell improved in vivo induced pluripotent stem cell innovation knock-down novel overexpression progenitor screening self-renewal virtual

Ablation Address Adult African African American Alloimmunization Antibodies Antibody Formation Antibody Specificity Antigens Area Biological Assay Blood Blood Banks Blood Group Antigens Blood donor Bone Marrow CRISPR/Cas technology Caring Cell Differentiation process Cell Line Cell surface Cells Chronic Clinical Complex Complication Custom Data Development Donor Selection Erythroblasts Erythrocyte Transfusion Erythrocytes Erythroid Erythroid Cells European Evaluation Exhibits Fetal Liver Frequencies Future GATA1 gene Gene Expression Genes Genetic Variation Genotype Globin Goals Grant Hematopoiesis High Prevalence Human In Vitro Incidence Individual Knock-out Laboratories Life Measures Megakaryocytes Methods Morbidity - disease rate Morphology Mus Outcome Patients Performance Phenotype Pluripotent Stem Cells Production Protocols documentation Reagent Research Personnel Safety Savings Serum Sickle Cell Anemia Source Standardization Stem cells Stroke prevention Stromal Cells Surface Antigens TP53 gene Techniques Technology Testing Therapeutic Transfusion Variant Yolk Sac base cost design fetal genetic variant genetically modified cells genome editing genome-wide human pluripotent stem cell improved in vivo induced pluripotent stem cell innovation knock-down novel overexpression progenitor screening self-renewal virtual

展开

项目摘要

ABSTRACT: OVERALL Red blood cell transfusion remains a life-saving therapy for patients with sickle cell disease (SCD). A major problem is the high rate of alloimmunization (antibody formation against transfused red cells) that occurs in transfused patients with SCD. Genetic diversity in blood group antigens in patients of African descent compared to the primarily European-based donor pool contributes to this high incidence and complexity of antibodies found in patients with SCD. Finding compatible red blood cell (RBC) units is often complicated by a lack of rare reagent RBCs to properly identify these complex antibody specificities. This complication delays care, increases costs, and makes transfusion therapy impossible for some patients. The ultimate goal of this proposal is to use human induced pluripotent stem cells (iPSCs) to produce standard and reliable red blood cell (RBC) reagents to resolve this major problem. We have designed a panel of iPSCs genetically engineered to express unique combinations of blood group antigens (customized iPSCs) that are difficult or virtually impossible to find in donor RBCs. RBC reagents produced from these customized iPSCs will provide the means to streamline and standardize antibody identification in alloimmunized patients, and ultimately can be used as “universal” donor cells for future therapeutic applications. Our efforts will address several existing challenges that include: i. insufficient or no living blood donors expressing the combinations of blood group antigens needed to resolve the complex antibody specificities in patients with SCD, ii. lack of iPSC differentiation protocols to produce definitive, adult-type RBCs without the use of serum or stromal cells, and iii. the prohibitively expensive manufacturing costs of iPSC-derived RBCs. In this U01 application, we propose three integrated Projects from a group of highly collaborative investigators with expertise in areas that can address all three challenges and will drive the field forward by providing innovative solutions to these current obstacles.

摘要：总体红细胞输血仍然是镰状细胞病（SCD）患者的挽救生命疗法。专业问题是出现在患有SCD的患者。非洲血统患者血型抗原的遗传多样性与主要的欧洲捐助池相比，这一高事件和复杂性 SCD患者发现的抗体。寻找兼容的红细胞（RBC）单位通常会因缺乏罕见的试剂RBC来正确识别这些复杂的抗体规格。这种并发症延迟护理，增加成本，并使某些患者无法输血疗法。最终目标建议是使用人类诱导的多能干细胞（IPSC）产生标准且可靠的红血细胞（RBC）试剂解决这一主要问题。我们设计了一组iPSCS的面板表达血型抗原（自定义IPSC）的独特组合，这些组合是困难或实际上是在捐助者RBC中找不到。这些自定义IPSC生产的RBC试剂将提供简化和标准化同种免疫患者抗体鉴定的手段，最终可以是用作未来治疗应用的“通用”供体细胞。我们的努力将解决一些现有的包括：i。表达血型组合的血液供体不足或没有活的献血者抗原需要解决SCD患者的复杂抗体规格。缺乏IPSC 分化方案可生产明确的成人型RBC，而无需使用血清或基质细胞，以及III。该禁止的IPSC衍生的RBC的制造成本极为昂贵。在此U01应用程序中，我们建议来自一群高度合作调查员的三个集成项目，在可以的领域具有专业知识解决所有三个挑战，并将通过为这些当前的创新解决方案提供创新的解决方案来推动该领域的前进障碍。