Correcting Aberrant Splicing of the Human CD22 Gene

纠正人类 CD22 基因的异常剪接

基本信息

批准号：
8648740
负责人：
LLOYD G MITCHELL
金额：
$ 22.5万
依托单位：
RETROTHERAPY, LLC
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8648740
关键词：
Acute Lymphocytic Leukemia Address Adolescent B-Lymphocytes Bone Marrow CD22 gene Cells Child Childhood Childhood Acute Lymphocytic Leukemia Defect Development Diagnosis Exons Failure Gene Targeting Genes Goals Growth Homeostasis Human In Vitro Lead Leukemic Cell Malignant Childhood Neoplasm Malignant Neoplasms Mus Mutation Newly Diagnosed Patients RNA RNA Splicing Receptors, Antigen, B-Cell Refractory Relapse Research Research Project Grants Resistance Reverse Transcriptase Polymerase Chain Reaction Signal Transduction Signal Transduction Pathway Specificity Specimen Survival Rate Technology Testing Therapeutic Time Trans-Splicing Translational Research Xenograft Model Xenograft procedure chemotherapy design effective therapy high risk in vivo in vivo Model innovation insight leukemia mutant outcome forecast pre-clinical public health relevance repaired self-renewal

项目摘要

DESCRIPTION (provided by applicant): B-precursor acute lymphoblastic leukemia (BPL) is the most common form of cancer in children and adolescents. This project addresses an urgent and unmet need for the treatment of aggressive, treatment refractory BPL. Two recent studies have found a deletion of CD22 exon 12 (CD22ΔE12) in primary leukemic cells in the vast majority of pediatric patients with poor prognosis, newly diagnosed, or relapsed BPL. RT-PCR analysis of primary leukemic cells in matched pair diagnosis vs. induction failure specimens, and diagnosis vs. 1st bone marrow relapse specimens provided direct evidence that the CD22ΔE12 genetic defect is detectable at the time of initial diagnosis in therapy-refractory pediatric ALL patients. Preliminary studies support the hypothesis that correction of CD22ΔE12 results in the loss of self-renewal capacity and significantly reduces the clonogenicity of leukemic cells. We intend to develop the therapeutic potential of an RNA technology that corrects expression of the mutant form of CD22 to generate a potent anti-leukemic activity. Functional testing will be performed in patient-derived BPL cells in vitro and in vivo, using a mouse/human xenograft model to identify 1-3 pre-clinical candidates. Successful completion of this project may lead to the development of a new, paradigm- shifting therapeutic innovation for BPL as well as other cancers associated with deletions in CD22.

描述（由申请人提供）：B 前体急性淋巴细胞白血病 (BPL) 是儿童和青少年中最常见的癌症形式，该项目解决了治疗侵袭性难治性 BPL 的迫切且未得到满足的需求。发现绝大多数预后不良、新诊断或复发的儿科患者的原代白血病细胞存在 CD22 外显子 12 (CD22ΔE12) 缺失对配对诊断与诱导失败标本以及诊断与第一次骨髓复发标本中原代白血病细胞的 BPL 分析提供了直接证据，表明在治疗难治性儿科的初始诊断时可检测到 CD22ΔE12 遗传缺陷。初步研究支持这样的假设：CD22ΔE12 的校正会导致自我更新能力的丧失，并显着降低白血病细胞的克隆性。纠正 CD22 突变形式的表达以产生有效的抗白血病活性的 RNA 技术的治疗潜力将在体外和体内对患者来源的 BPL 细胞进行功能测试，并使用小鼠/人类异种移植模型来鉴定。 1-3 临床前候选者。该项目的成功完成可能会导致针对 BPL 以及与 CD22 缺失相关的其他癌症开发新的、范式转变的治疗创新。