Cell and Gene Therapy for Nonmalignant Blood Disorders

 描述（由申请人提供）：我们提出了一个高度协同和创新的基础和临床研究计划，以通过异基因造血细胞移植（HCT）和基因治疗改善原发性免疫缺陷疾病和血红蛋白病患者的治疗。我们试图通过引入安全，无毒的预处理方案和避免移植物抗病毒的新方法来实现这一目标。宿主病（GVHD）。该方案包括由四个核心支助的三个项目。临床项目1有三个目标，第一个目标是在HLA匹配的HCT受体中完成，其余两个目标是在给予HLA半相合移植物的患者中完成。目的之一是通过使用与针对CD 45的单克隆抗体（MAb）偶联的α粒子发射放射性核素<$-211（211 At）的靶向照射来避免当前预处理方案的毒性，特别是继发性癌症。目的二是利用自杀基因修饰的T细胞（BPX 501）与CD 34+选择的HLA-半相合干细胞一起沿着给予的多中心试验，以便在降低强度的预处理后实现植入并避免随后的GVHD。这将确保几乎每个患有候选疾病的患者，特别是来自少数民族群体的患者，都可以接受同种异体HCT。第三个目标是纳入211 At-抗CD 45单克隆抗体，以防止HLA-半相合移植物的排斥反应，这是一个对镰状细胞性贫血患者特别重要的目标。这两个临床前项目使用HCT犬模型，相互之间以及与临床项目紧密结合。项目2主要关注 四个目标。第一种方法使用211 At标记的抗CD 45放射性标记单克隆抗体作为丙酮酸激酶（PK）缺乏症犬的HCT条件，作为人血红蛋白病模型。第二种方法是使用211 At标记的抗CD 45单克隆抗体处理X连锁严重联合免疫缺陷（SCID-X1）犬的DLA-半相合移植物，以确保持续的多谱系供体细胞植入。第三个目的是克服输血诱导的致敏性，从而降低使用211 At标记的单克隆抗体在DLA相同设置中的移植物排斥反应的风险。第四个目标将研究离体扩增的DLA相同的CD 34+干细胞在没有GVHD的情况下实现持续植入的能力。项目3将重点关注开发新的、毒性较小的基因治疗预处理方案、造血干/祖细胞（HSC）的扩增以及慢病毒载体的体内递送。将追求三个目标。第一个将评估在用白消安、曲磺凡或211 At标记的抗CD 45单抗调节后基因修饰的HSC的植入。它还将探索自杀基因安全开关，并进行广泛的克隆分析。目的二将评估造血干细胞的体外扩增是否可以改善非清髓性预处理后的植入。目的三将评估扩增和基因校正的HSC是否可以在最小条件处理后纠正犬SCID-X1和PK模型中的遗传疾病。 高度协同的计划提出了创新的，改变实践的基础和临床研究，旨在显着改善异基因造血细胞移植（HCT）和遗传性非恶性血液病（包括原发性免疫缺陷和血红蛋白病）基因治疗的结果。HLA半相合家族成员移植的成功方案的开发将确保几乎每一个患有候选疾病的患者，特别是来自少数民族群体的患者，都可以成为同种异体HCT的接受者。 (End摘要） 项目1：纠正血液疾病的细胞疗法（STORB，Rainer F.）

 DESCRIPTION (provided by applicant): We propose a highly synergistic and innovative program of basic and clinical research to improve treatment of patients with primary immunodeficiency disorders and hemoglobinopathies by allogeneic hematopoietic cell transplantation (HCT) and gene therapy. We seek to accomplish this by introducing safe, non-toxic conditioning regimens and novel ways of averting graft-vs.-host disease (GVHD). The Program consists of three projects supported by four cores. The clinical Project 1 has three aims, the first to be accomplished in recipients of HLA-matched HCT and the remaining two in patients given HLA-haploidentical grafts. Aim one is to avoid toxicities of current conditioning regimens, especially secondary cancer, by using targeted irradiation with the alpha-particle emitting radionuclide astatine-211 (211At) coupled to a monoclonal antibody (MAb) directed at CD45. Aim two is a multicenter trial exploiting suicide gene modified T cells (BPX 501) given along with CD34+ selected HLA-haploidentical stem cells in order to both accomplish engraftment after reduced- intensity conditioning and avert subsequent GVHD. This would assure that virtually every patient with a candidate disease, especially patients from ethnic minority groups, can receive allogeneic HCT. The third aim is to incorporate 211At-anti-CD45 MAb to prevent rejection of HLA-haploidentical grafts, a goal particularly important for patients with sickle cell anemia. The two preclinical projects, using a canine model of HCT, are closely integrated with each other as well as with the clinical project. Specifically, Project 2 focuses on four aims. The first uses a 211At-labeled anti-CD45 radiolabeled MAb as conditioning for HCT in dogs with pyruvate kinase (PK) deficiency as model for human hemoglobinopathies. The second tackles DLA-haploidentical grafts in dogs with X-linked severe combined immunodeficiency (SCID-X1) using the 211At-labeled anti-CD45 MAb in order to assure sustained multi-lineage donor cell engraftment. The third aims to overcome transfusion- induced sensitization and consequently reduce the risk of graft rejection in the DLA-identical setting using 211At-labeled MAb. The fourth aim will study ex vivo-expanded DLA-identical CD34+ stem cells for their ability to achieve sustained engraftment without GVHD. Project 3 will focus on the development of new and less toxic conditioning regimens for gene therapy, expansion of hematopoietic stem/progenitor cells (HSCs) and on in vivo delivery of lentiviral vectors. Three aims will be pursued. The first will evaluate engraftment of gene- modified HSCs following conditioning with busulfan, treosulfan or 211At-labeled anti-CD45 MAb. It will also explore a suicide-gene safety switch and carry out extensive clonal analyses. Aim two will evaluate whether ex vivo expansion of HSCs can improve engraftment after non-myeloablative conditioning. Aim three will evaluate whether expanded and gene-corrected HSCs can correct genetic diseases in the canine SCID-X1 and PK models after minimal conditioning. The highly synergistic Program proposes innovative, practice-changing, basic and clinical research aimed at dramatically improving outcomes of allogeneic hematopoietic cell transplantation (HCT) and gene therapy for inherited nonmalignant blood diseases including primary immunodeficiencies and hemoglobinopathies. The development of successful regimens for grafts from HLA-haploidentical family members would assure that virtually every patient with a candidate disease, especially patients from ethnic minority groups, could become a recipient of allogeneic HCT. (End of Abstract) PROJECT 1: CELL THERAPY FOR CORRECTION OF BLOOD DISORDERS (STORB, RAINER F.)