A first-in-human phase 0 clinical study of RNA interference-based spherical nucleic acids in patients with recurrent glioblastoma.
A first-in-human phase 0 clinical study of RNA interference-based spherical nucleic acids in patients with recurrent glioblastoma.
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DOI：
10.1126/scitranslmed.abb3945
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发表时间：
2021-03-10
影响因子：
17.1
通讯作者：
Stegh AH
中科院分区：
文献类型：
--
作者：
Kumthekar P;Ko CH;Paunesku T;Dixit K;Sonabend AM;Bloch O;Tate M;Schwartz M;Zuckerman L;Lezon R;Lukas RV;Jovanovic B;McCortney K;Colman H;Chen S;Lai B;Antipova O;Deng J;Li L;Tommasini-Ghelfi S;Hurley LA;Unruh D;Sharma NV;Kandpal M;Kouri FM;Davuluri RV;Brat DJ;Muzzio M;Glass M;Vijayakumar V;Heidel J;Giles FJ;Adams AK;James CD;Woloschak GE;Horbinski C;Stegh AH
由于血脑/血肿瘤屏障的存在，颅内肿瘤部位的治疗途径有限，缺乏精确的治疗方法，导致胶质母细胞瘤（GBM）成为最难有效治疗的癌症之一。我们开发了一种新的精确医学方法用于GBM治疗，该方法涉及使用基于脑渗透RNA干扰（RNAi）的球形核酸（SNA）。在这项研究中，我们使用的SNA组成的金纳米粒子核共价结合径向取向和密集包装的siRNA寡核苷酸。基于之前的临床前评价，我们在非人灵长类动物中进行了毒理学和毒代动力学研究，并进行了一项单臂、开放标签0期首次人体试验（NCT 03020017），以确定全身给药携带GBM致癌基因Bcl 2Like 12（Bcl 2L 12）特异性siRNA的SNA的安全性、药代动力学、瘤内蓄积和基因抑制活性。用静脉内施用siBcl 2L 12-SNA（药物名称：NU-0129）治疗复发性GBM患者，剂量对应于无观察到的不良事件水平（NOAEL）的1/50，随后进行肿瘤切除。安全性评估显示无显著的治疗相关毒性。切除的GBM组织的电感耦合等离子体质谱、X射线荧光显微镜和银染色证明，静脉内施用的SNA到达患者肿瘤，在肿瘤相关内皮、巨噬细胞和肿瘤细胞中观察到金（Au）富集。神经胶质瘤细胞中NU-0129的摄取与肿瘤相关的Bcl 2L 12蛋白表达的显著降低相关，如通过比较NU-0129治疗的复发性与匹配的原发性（即，未治疗的）肿瘤。我们的研究结果确立SNA纳米复合物作为GBM系统治疗的脑渗透精密医学方法。这项基于基因调控RNA干扰的球形核酸的首次人体0期研究表明，SNA纳米缀合物代表了治疗胶质母细胞瘤的潜在安全和脑渗透的精确医学方法。
The lack of precision therapies combined with limited therapeutic access to intracranial tumor sites due to the presence of the blood-brain/blood-tumor barriers have contributed to glioblastoma (GBM) being one of the most difficult cancers to effectively treat. We have developed a novel precision medicine approach for GBM treatment that involves the use of brain-penetrant RNA interference (RNAi)-based spherical nucleic acids (SNAs). In this study, we used SNAs consisting of gold nanoparticle cores covalently conjugated with radially oriented and densely packed siRNA oligonucleotides. Based upon previous preclinical evaluation, we conducted toxicology and toxicokinetic studies in non-human primates, and a single-arm, open-label phase 0 first-in-human trial (NCT03020017) to determine safety, pharmacokinetics, intratumoral accumulation and gene-suppressive activity of systemically administered SNAs carrying siRNA specific for the GBM oncogene Bcl2Like12 (Bcl2L12). Patients with recurrent GBM were treated with intravenous administration of siBcl2L12-SNAs (drug moniker: NU-0129), at a dose corresponding to 1/50th of the no-observed-adverse-event-level (NOAEL), followed by tumor resection. Safety assessment revealed no significant treatment-related toxicities. Inductively coupled plasma mass spectrometry, X-ray fluorescence microscopy, and silver staining of resected GBM tissue demonstrated that intravenously administered SNAs reached patient tumors, with gold (Au) enrichment observed in the tumor-associated endothelium, macrophages and tumor cells. NU-0129 uptake into glioma cells correlated with significant reduction in tumor-associated Bcl2L12 protein expression, as indicated by comparison of NU-0129-treated recurrent vs. matched primary (i.e., untreated) tumor. Our results establish SNA nanoconjugates as a brain-penetrant precision medicine approach for the systemic treatment of GBM. This first-in human phase 0 study of gene-regulatory RNA interference-based Spherical Nucleic Acids demonstrates that SNA nanoconjugates represent a potentially safe and brain-penetrant precision medicine approach for the treatment of glioblastoma.
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