Delivery of small-interfering RNA (siRNA) to the brain.
Delivery of small-interfering RNA (siRNA) to the brain.
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DOI：
10.1517/13543770802680195
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发表时间：
2009-02
影响因子：
6.6
通讯作者：
Mathupala SP
中科院分区：
文献类型：
--
作者：
Mathupala SP
治疗中枢神经系统（CNS）疾病的药物递送有两个基本困难，一是药物通过血脑屏障（BBB）的全身递送，二是药物靶向大脑内的特定组织或细胞。随着利用RNA干扰（RNAi）触发病变组织内基因特异性沉默的基于RNA的治疗方法的出现和前景，克服这些障碍的必要性变得更加迫切。大多数临床前和临床研究都是利用侵入性的、脑内的RNA递送到靶组织。因此，需要开发方法，以促进通过全身途径将具有治疗意义的大量RNA递送到中枢神经系统，并在中枢神经系统组织中引发具有临床意义的RNAi效应。细胞穿透肽（CPPs）是“分子递送载体”，可以穿过细胞膜并共同运输肽或多核苷酸。本发明研究了1)CPP-RNA双链在向中枢神经系统组织递送RNA中的作用，以及2)一旦CPP-RNA双链被中枢神经系统细胞内化，细胞介导的RNA有效载荷释放。本发明和其中列出的实施例概述了在未来临床环境中可适用于治疗性RNA向中枢神经系统的非侵入性、系统性递送的分子工具。
Two fundamental difficulties in the delivery of drugs to treat central nervous system (CNS) diseases are the systemic delivery of therapeutics across the bloodbrain-barrier (BBB), and the targeting of drugs to specific tissues or cells within the brain. With the advent and promise of RNA-based therapeutics that utilize RNA interference (RNAi) to trigger specific silencing of genes within diseased tissues, the necessity to surmount such obstacles has become even more urgent. Most pre-clinical and clinical studies on delivery of RNAi to the CNS have utilized invasive, intra-cerebral delivery of RNA to the targeted tissue. Thus, methods need to be developed to facilitate delivery of therapeutically significant quantities of RNA to the CNS via the systemic route, and to elicit clinically significant RNAi effects within the CNS tissues. Cell-penetrating-peptides (CPPs) are ‘molecular delivery vehicles’ that can traverse cell membranes and co-transport peptides or polynucleotides. The present invention examines 1) the utility of CPP-RNA duplexes for delivery of RNA to CNS tissues and, 2) cell-mediated release of the RNA payload once the CPP-RNA duplex is internalized by the CNS cells. The invention and embodiments listed therein outline molecular tools that can be adapted for non-invasive, systemic delivery of therapeutic RNA to the CNS in a future clinical setting.
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影响因子：
5.3
作者：
Davidson, TJ;Harel, S;Troy, CM
通讯作者：
Troy, CM
影响因子：
--
作者：
Chiu, YL;Ali, A;Rana, TM
通讯作者：
Rana, TM
影响因子：
3.5
作者：
Muratovska, A;Eccles, MR
通讯作者：
Eccles, MR
影响因子：
2.8
作者：
Lesniak, MS
通讯作者：
Lesniak, MS
影响因子：
3.5
作者：
Zhang, Y;Boado, RJ;Pardridge, WM
通讯作者：
Pardridge, WM