PDF(Pubmed)
Abstract：
Tyrosine kinase inhibitors have been the standard treatment for patients with Philadelphia chromosome-positive (Ph+) leukemia. However, a series of issues, including drug resistance, relapse and intolerance, are still an unmet medical need. Here, we report the targeted siRNA-based lipid nanoparticles in Ph+ leukemic cell lines for gene therapy of Ph+ leukemia, which specifically targets a recently identified NEDD8 E3 ligase RAPSYN in Ph+ leukemic cells to disrupt the neddylation of oncogenic BCR-ABL. To achieve the specificity for Ph+ leukemia therapy, a single-chain fragment variable region (scFv) of anti-CD79B monoclonal antibody was covalently conjugated on the surface of OA2-siRAPSYN lipid nanoparticles to generate the targeted lipid nanoparticles (scFv-OA2-siRAPSYN). Through effectively silencing RAPSYN gene in leukemic cell lines by the nanoparticles, BCR-ABL was remarkably degraded accompanied by the inhibition of proliferation and the promotion of apoptosis. The specific targeting, therapeutic effects and systemic safety were further evaluated and demonstrated in cell line-derived mouse models. The present study has not only addressed the clinical need of Ph+ leukemia, but also enabled gene therapy against a less druggable target.
摘要：
酪氨酸激酶抑制剂已成为费城染色体阳性（Ph）白血病患者的标准治疗方法。然而,一系列的问题,包括耐药性,复发和不容忍，仍然是未满足的医疗需求。这里,我们报道了Ph白血病细胞系中基于靶向siRNA的脂质纳米颗粒用于Ph白血病的基因治疗，特异性靶向Ph白血病细胞中最近鉴定的NEDD8E3连接酶RAPSYN，以破坏致癌BCR-ABL的neddylation。为了实现Ph+白血病治疗的特异性，将抗CD79B单克隆抗体的单链片段可变区(scFv)共价缀合在OA2-siRAPSYN脂质纳米颗粒的表面,以生成靶向脂质纳米颗粒(scFv-OA2-siRAPSYN).通过纳米颗粒有效沉默白血病细胞系中的RAPSYN基因,BCR-ABL明显降解，同时抑制增殖和促进凋亡。具体的目标，在细胞系来源的小鼠模型中进一步评估和证明了治疗效果和系统安全性.本研究不仅解决了Ph+白血病的临床需要，但也使基因疗法对一个不太容易用药的目标。
