STEM CELL THERAPY OF CONGENITAL DEFECTS IN HEMATOPOIESIS

(改编自申请人的摘要)本SCOR的总体目标 建议制定临床翻译策略以纠正 人类造血干细胞的先天性疾病。认识 病理生理和临床情况的多样性是 可能需要不止一种治疗方法，我们选择了 同时承担基础科学和临床翻译工作 两个领域的研究。第一种方法将重点放在全球 半相合异基因移植替代造血干细胞的研究 骨髓移植。为了实现这一目标，项目4、5和 6将试图减少或改善发病率和并发症 通过尝试麻木或克隆删除移植物对宿主疾病 半相合供者骨髓中存在宿主同种异体反应性T细胞。 这些研究将跨越基本的实验室调查，包括小鼠和人类 临床前研究和人体实验。如果成功， 半相合异基因骨髓移植可以提供一种 为大多数慢性粒细胞白血病患者提供现成的供体骨髓来源 先天性造血干细胞疾病。第二种方法 将专注于制定安全、高效和 有效矫正先天性造血干细胞疾病 通过将基因转移到干细胞中。为了实现这一目标，项目1、2、 3和5将确定隔离和潜在扩展的最佳方法 干细胞，建立优化干细胞基因转移的条件 细胞，确定将基因转移到 自体干细胞在小鼠临床前的体外测试方法学 方法评价基因转移的有效性和最优化 自体干细胞植入的预适应方案及矫正 小鼠模型中的先天性干细胞疾病。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 技术将继续进行更复杂的获得性基因转移研究 或者先天性疾病。这项提议的力量在于它的 专注于临床实验。通过选择尝试 两种截然不同但潜在有效的战略，我们将在 在第一年进行临床试验，毫无疑问，将能够 通过完成对这些方法的相对优点进行评估 这个项目的。这一SCOR在其产生之初就具有高度的互动性。 为了确保它的成功，我们已经召集了高度多样化的 由分子和细胞生物学家组成的交互式协作团队， 免疫学家、移植生物学家、血液学家和临床医生 有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.