Correcting Aberrant Splicing of the Human CD22 Gene

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的迫切和未满足的需求。最近的两项研究发现，在绝大多数预后不良、新诊断或复发BPL的儿科患者的原发性白血病细胞中，CD22外显子12缺失（CD22ΔE12）。RT-PCR分析配对对诊断与诱导失败标本、诊断与首次骨髓复发标本中的原代白血病细胞提供了直接证据，证明在治疗难治性儿科ALL患者初次诊断时可检测到CD22ΔE12遗传缺陷。初步研究支持这样的假设，即纠正CD22ΔE12会导致自我更新能力的丧失，并显著降低白血病细胞的克隆原性。我们打算开发一种RNA技术的治疗潜力，这种技术可以纠正CD22突变形式的表达，从而产生一种有效的抗白血病活性。将在体外和体内对患者来源的BPL细胞进行功能测试，使用小鼠/人类异种移植模型确定1-3个临床前候选细胞。这个项目的成功完成可能会导致BPL以及其他与CD22缺失相关的癌症的一种新的、范式转变的治疗创新的发展。

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.