STEM CELL THERAPY OF CONGENITAL DEFECTS IN HEMATOPOIESIS

（摘自申请人摘要）本SCOR的总体目标 建议是制定临床翻译策略， 人类造血干细胞的先天性疾病。认识 病理生理学和临床情况的多样性 可能需要一种以上的治疗方法，我们选择了 同时进行基础科学和临床转化 研究在两个领域。第一种方法将侧重于全球 用半相合的同种异体造血干细胞替代造血干细胞 骨髓移植为实现这一目标，项目4、5和 6将试图减少或改善的发生率和并发症 移植物抗宿主病的研究 宿主同种异体反应性T细胞存在于半相合供体骨髓中。 这些研究将涵盖基本的实验室研究，鼠和人类 临床前研究和人体实验。如果成功， 单倍相合异基因骨髓移植可提供 对于大多数患有骨髓瘤的患者来说， 造血干细胞的遗传性疾病第二种方法 将专注于制定安全，高效， 有效纠正造血干细胞先天性疾病， 通过基因转移到干细胞中。为了实现这一目标，项目1、2、 3和5将确定分离和潜在扩展的最佳方法 干细胞，建立优化基因转移到干细胞中条件 细胞，确定将基因转移到 自体干细胞，临床前小鼠体外试验方法 方法来评估基因转移的功效和最佳的 自体干细胞移植的预处理方案， 在小鼠模型中干细胞的先天性疾病。最后这些 研究将提供纠正一个或多个先天性 人类造血干细胞的疾病，并将提供 技术进行基因转移研究更复杂的获得性 或先天性疾病。这一建议的力量在于其 专注于临床实验。通过选择尝试 两个不同的，但可能有效的战略，我们将在 临床实验，毫无疑问，将能够 评估这些方法的相对优点， of this project项目.该SCOR在其起源中具有高度互动性。 为了确保它的成功，我们聚集了一个高度多样化的， 由分子和细胞生物学家组成互动协作团队， 免疫学家、移植生物学家、血液学家和临床医生， 丰富的翻译经验来实现这些目标。

(Adapted from the applicant's abstract) The overall goal of this SCOR proposal is to develop clinical translational strategies to correct congenital diseases of the human hematopoietic stem cell. Recognizing that the diversity of pathophysiologies and clinical circumstances are likely to require more than one therapeutic approach, we have elected to undertake concurrent basic scientific and clinical translational studies in two arenas. The first approach will focus upon global replacement of the hematopoietic stem cell by haploidentical allogeneic bone marrow transplantation. To achieve this goal, Projects 4, 5 and 6 will attempt to reduce or ameliorate the incidence and complications of graft vs host disease by attempting to anergize or clonally delete host alloreactive T cells present in haploidentical donor bone marrow. These studies will span basic laboratory investigations, murine and human preclinical studies, and human experimentation. If successful, haploidentical allogenic bone marrow transplantation could provide a readily available source of donor bone marrow for most patients with congenital diseases of the hematopoietic stem cell. The second approach will focus upon developing strategies to safely, efficiently, and effectively correct congenital diseases of the hematopoietic stem cell by gene transfer into stem cells. To achieve this goal, Projects 1, 2, 3 and 5 will determine optimal methods to isolate and potentially expand stem cells, establish conditions which optimize gene transfer into stem cells, determine the optimal methodologies to transfer genes into autologous stem cells, test in vitro methodologies in murine preclinical methods to evaluate both efficacy of gene transfer and optimal conditioning regimens for autologous stem cell engraftment and correct congenital diseases of the stem cell in murine models. Finally, these studies will provide methodologies to correct one or more congenital diseases of the human hematopoietic stem cell and will provide the technology to proceed to gene transfer studies of more complex acquired or congenital disorders. The strength of this proposal lies in its focused drive toward clinical experimentation. By electing to attempt two distinct, yet potentially efficacious strategies, we will be in clinical experimentation by year 1 and, without question, will be able to evaluate the relative merits of these approaches by the completion of this project. This SCOR has been highly interactive in its genesis. To insure its success, we have assembled a highly diverse yet interactive collaborative team of molecular and cell biologists, immunologists, transplant biologists, hematologists, and clinicians with extensive translational experience to accomplish these goals.