CORRECTION OF CONGENITAL DISEASES BY STEM CELL THERAPY

通过干细胞疗法纠正先天性疾病

• 批准号: 6202406
• 负责人: DAVID G. NATHAN
• 金额: $ 26.68万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2000-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6202406
• 关键词: anergy; bone marrow transplantation; clinical trials; congenital blood disorder; gene expression; gene therapy; haploidy; hematopoietic stem cells; homologous transplantation; human subject; human therapy evaluation; isoantigen; multidrug resistance; neoplasm /cancer remission /regression; ovary neoplasms; tissue donors; transfection /expression vector

(Adapted from the applicant's abstract) Excluding allogeneic bone marrow transplantation (alloBMT), the treatment of congenital diseases of the stem cell is by definition palliative. The clinical course of patients (pts) with most of these disorders is typified by chronic morbidity secondary to both the pathophysiology of the disorder and the sequelae of available therapy. The goal of this project is the translation of the basic and preclinical studies undertaken in all previous sections as they culminate in clinical experiments designed to correct congenital diseases by utilizing stem cell therapy. Two approaches will be employed which have the common feature of utilization of the totipotent stem cell as a vehicle to produce a missing protein in sufficient quantities to reverse a clinical phenotype. The first approach relies on replacement of the entire hematopoietic system, including the stem cell. Specifically, we propose to extend the availability of alloBMT as a therapeutic option by facilitating the use of haploidentical family members as donors. The second approach is based upon the principle that it may be possible to stably introduce a functional version of a defective gene into the totipotent stem cell. Specifically, we propose to first modify primitive hematopoietic cells of pts ex vivo by transfer of functional genes using viral vectors and then attempt to reconstitute hematopoiesis and normal gene expression and function. To achieve these objectives, we propose two specific aims. First, we plan to undertake clinical trials to demonstrate the feasibility, safety and efficacy of manipulations designed to either anergize or delete donor BM T cells specific for host alloantigen to ameliorate GVHD in pts undergoing haploidentical BMT. In these studies, we plan to immediately enter the clinic attempting to induce anergy to host alloantigen in donor BMT cells in selected pts with congenital diseases eligible for haplomismatched BMT. As preclinical and clinical studies dictate, we will pilot attempts to clonally delete donor T cells specific for host alloantigens in selected pts with hematologic malignancies eligible for haplomismatched BMT and then extend this approach to selected pts with congenital diseases. Second, we plan to undertake a series of pilot clinical studies to establish the feasibility and safety of methodologies which will lead to long term expression of transferred genes in human hematopoietic stem cells. In order to determine whether this manipulation confers stem cell resistance to high dose chemotherapy at the time of relapse, we plan to introduce the MDR-1 gene into the donor BM of pts at high risk for relapse after undergoing 1) alloBMT for hematologic malignancies and 2) autologous BMT for ovarian carcinoma. Ultimately, we will attempt to cure hematopoietic stem cells diseases by gene therapy. The development of these two parallel approaches should yield the most flexibility in eventual triage of therapy for specific pts and disorders. The evolution of these studies is highly dependent on the success of all previous projects.

（改编自申请人摘要）不包括同种异体骨髓 移植（alloBMT），治疗先天性疾病， 从定义上讲，干细胞是姑息性。患者的临床过程 (pts)大多数这些疾病的典型特征是慢性病 继发于疾病的病理生理学和后遗症 可用的治疗方法。这个项目的目标是翻译 在前面所有章节中进行的基础和临床前研究 因为他们在临床实验中达到了顶峰， 干细胞治疗的方法两种方法将是 使用具有利用全能性的共同特征的 干细胞作为一种载体， 量来逆转临床表型。第一种方法依赖于 包括干细胞在内的整个造血系统 cell.具体来说，我们建议扩展alloBMT的可用性， 通过促进使用单倍体相合家族的治疗选择 作为捐助者。第二种方法基于这样的原则， 可以稳定地引入 有缺陷的基因进入全能干细胞。具体来说，我们建议 为了首先通过转移离体修饰PTS的原始造血细胞 功能性基因，然后尝试重组 造血和正常基因表达和功能。实现这些 我们提出了两个具体目标。首先，我们计划 临床试验，以证明的可行性，安全性和有效性 设计用于使供体BM T细胞失活或缺失的操作 特异于宿主同种异体抗原以改善经历GVHD的患者中的GVHD 单倍体相同的骨髓移植。在这些研究中，我们计划立即进入 临床尝试在供体BMT中诱导对宿主同种异体抗原的无反应性 在选定的患有先天性疾病的患者中， 单倍性不匹配骨髓移植。根据临床前和临床研究的要求，我们 将尝试克隆删除对宿主特异性的供体T细胞， 在选定的符合条件的血液恶性肿瘤患者中的同种异体抗原 单倍型不匹配的BMT，然后将这种方法扩展到选定的患者， 先天性疾病。第二，我们计划进行一系列试点， 临床研究，以确定可行性和安全性 方法，这将导致长期的表达转移 人类造血干细胞中的基因。为了确定是否 这种操作赋予干细胞对高剂量化疗的抗性 在复发时，我们计划将MDR-1基因导入 接受1）alloBMT后复发高风险患者的供体BM， 血液恶性肿瘤和2）自体骨髓移植卵巢癌。 最终，我们将尝试治愈造血干细胞疾病 通过基因疗法。这两种并行方法的发展 应该在最终的治疗分类中产生最大的灵活性， 特定患者和疾病。这些研究的进展是高度 这取决于之前所有项目的成功。