Bone marrow transplant without cytoreductive conditioning to cure Cooleys anemia

不进行细胞减灭预处理的骨髓移植可治愈库利斯贫血

• 批准号: 8911958
• 负责人: Jonathan Russell Lockhart
• 金额: $ 3.33万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-03 至 2018-04-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8911958
• 关键词: Adult; Adverse effects; Allogeneic Bone Marrow Transplantation; Allogenic; Anemia; Animal Model; Antibodies; Blood Transfusion; Bone Marrow; Bone Marrow Cells; Bone Marrow Purging; Bone Marrow Transplantation; Cell Therapy; Cells; Cessation of life; Childhood; Chimerism; Clinical; Clinical Management; Clinical Trials; Complication; Cooley' s anemia; Defect; Development; Disease; Dose; Engraftment; Erythrocytes; Erythropoiesis; Genes; Globin; Goals; Graft Rejection; Haplotypes; Hematological Disease; Hematopoietic; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Hemoglobin; Hemoglobinopathies; Hereditary Disease; Homologous Transplantation; Human; IL2RB gene; Immunosuppression; Inbred BALB C Mice; Individual; Inherited; Laboratories; Life; Marrow; Measures; Modality; Modeling; Monitor; Morbidity - disease rate; Mus; Mutation; National Heart, Lung, and Blood Institute; Newborn Infant; Normal Range; Pathology; Patients; Peripheral; Pre-Clinical Model; Procedures; Production; Protocols documentation; Quality of life; Regimen; TNFSF5 gene; Testing; Thalassemia; Therapeutic; Transfusion; Transgenic Mice; Transgenic Organisms; Transplantation; Transplantation Conditioning; Work; beta Globin; beta Thalassemia; blood resource; conditioning; diprotin A; graft vs host disease; improved; indexing; iron chelation therapy; mortality; mouse model; novel; pre-clinical; preclinical study; public health relevance; pup; reconstitution

 DESCRIPTION (provided by applicant): ß-thalassemia is a group of inherited blood disorders that result in defects in ß-globin chain production. Cooley's anemia (CA), or ß-thalassemia major, is the most severe form of the disease and occurs when an individual has mutations in both copies of the adult ß-globin gene. Patients with CA fail to make adult hemoglobin, have ineffective erythropoiesis, suffer from severe anemia, and are transfusion dependent for life. Currently, allogeneic bone marrow transplantation (BMT) is the only cure; however, few patients have suitable donors for this high morbidity/mortality procedure. This application outlines studies to establish a new BMT protocol that avoids the potentially lethal myeloablative conditioning of standard BMT. Preliminary studies have demonstrated the feasibility of using a non-cytoreductive conditioning regimen to rescue a preclinical humanized mouse model of CA from lethal anemia. These studies apply to several NHLBI Division of Blood Diseases and Resources stated goals: improving thalassemia treatment and management; development of hematopoietic transplantation; developing animal models for preclinical studies; and testing of novel cell-based therapies for the correction of thalassemia. The first main objective and specific aim of this project is to rescue humanized CA mice from lethal anemia by the use of non-cytoreductive bone marrow transplantation from a MHC-mismatched donor. The next main objective and specific aim is to determine the effect of adding an additional antibody treatment to the non- cytoreductive conditioning regimen. This study will employ a preclinical model of humanized CA by monitoring survival, HSC engraftment, disease and treatment-related pathology, and the donor marrow cell dose required after non-cytoreductive conditioned BMT. Together, these objectives would increase the clinical feasibility of utilizing bone marrow transplantation without cytoreductive conditioning to cure CA in human patients. Successful completion of the aims of this project will have a significant impact on the clinical management of CA patients. Furthermore, these ideas may be translatable to other hemoglobinopathies and blood disorders. The objectives in this proposal are the next step in developing a safe treatment for all patients with CA.

 描述（由申请人提供）：β-地中海贫血是一组遗传性血液疾病，导致β-珠蛋白链产生缺陷。库利氏贫血（CA），或重型β-地中海贫血，是最严重的形式的疾病，并发生时，一个人有突变的两个副本的成人β-珠蛋白基因。患有CA的患者不能制造成人血红蛋白，具有无效的红细胞生成，患有严重贫血，并且终生依赖输血。目前，同种异体骨髓移植（BMT）是唯一的治愈方法;然而，很少有患者有合适的供体用于这种高发病率/死亡率的手术。该应用程序概述了研究 建立一种新的BMT方案，避免了标准BMT的潜在致命的清髓性条件。初步研究已经证明了使用非细胞减少性预处理方案从致死性贫血中拯救CA的临床前人源化小鼠模型的可行性。这些研究适用于几个NHLBI血液疾病和资源部规定的目标：改善地中海贫血的治疗和管理;发展造血移植;开发临床前研究的动物模型;以及测试用于纠正地中海贫血的新型细胞疗法。本项目的第一个主要目的和具体目标是通过使用来自MHC错配供体的非细胞减少性骨髓移植来拯救人源化CA小鼠免于致死性贫血。下一个主要目的和具体目标是确定向非细胞减少性预处理方案中添加额外抗体治疗的效果。本研究将采用人源化CA的临床前模型，通过监测存活率、HSC植入、疾病和治疗相关病理以及非细胞减少性条件BMT后所需的供体骨髓细胞剂量。总之，这些目标将增加利用骨髓移植的临床可行性， 在人类患者中治疗CA的细胞减少性调节。本项目目标的成功完成将对CA患者的临床管理产生重大影响。此外，这些想法可能会转化为其他血红蛋白病和血液疾病。该提案的目标是为所有CA患者开发安全治疗的下一步。