Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles.
Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles.
复制标题
作者：
设计用于RNA干扰（RNAi）途径的治疗方法有可能为患者提供新的、主要的治疗方法。Fire等人首先证明了长双链RNA在秀丽隐杆线虫中介导RNAi， Elbashir等人通过证明小干扰RNA （sirna：约21个碱基对双链RNA）可以在哺乳动物细胞中诱导RNAi而不产生干扰素反应，开辟了将RNAi用于人类治疗的途径。我们目前正在进行第一项人体I期临床试验，涉及使用靶向纳米颗粒递送系统对实体癌患者进行siRNA的系统给药。在这里，我们提供了从递送的siRNA诱导RNAi在人类中的作用机制的证据。治疗后对黑色素瘤患者进行的肿瘤活检显示：(1)细胞内局部存在纳米颗粒，其数量与所施用纳米颗粒的剂量水平相关（这是首次系统递送任何种类的纳米颗粒），(2)与给药前组织相比，特异性mRNA（核糖核苷酸还原酶M2亚基（RRM2））和蛋白质（RRM2）均有所减少。最重要的是，我们检测到mRNA片段的存在，证明siRNA介导的mRNA切割发生在RNAi机制预测的位点，来自接受最高剂量纳米颗粒的患者。总的来说，这些数据表明，siRNA系统地施用于人类可以通过RNAi作用机制产生特定的基因抑制（mRNA和蛋白质的减少）。
Therapeutics that are designed to engage RNA interference (RNAi) pathways have the potential to provide new, major ways of imparting therapy to patients. Fire et al. first demonstrated that long, double stranded RNAs mediate RNAi in Caenorhabditis elegans, and Elbashir et al. opened the pathway to the use of RNAi for human therapy by showing that small interfering RNAs (siRNAs: ca. 21 base pair double stranded RNA) can elicit RNAi in mammalian cells without producing an interferon response. We are currently conducting the first-in-human Phase I clinical trial involving the systemic administration of siRNA to patients with solid cancers using a targeted, nanoparticle delivery system. Here we provide evidence of inducing an RNAi mechanism of action in a human from the delivered siRNA. Tumor biopsies from melanoma patients obtained after treatment reveal: (i) the presence of intracellularly-localized nanoparticles in amounts that correlate with dose levels of the nanoparticles administered (this is a first for systemically delivered nanoparticles of any kind), and (ii) reduction in both the specific mRNA (M2 subunit of ribonucleotide reductase (RRM2)) and the protein (RRM2) when compared to pre-dosing tissue. Most importantly, we detect the presence of an mRNA fragment that demonstrates siRNA mediated mRNA cleavage occurs specifically at the site predicted for an RNAi mechanism from a patient who received the highest dose of the nanoparticles. These data when taken in total demonstrate that siRNA administered systemically to a human can produce a specific gene inhibition (reduction in mRNA and protein) by an RNAi mechanism of action.
登录
查看更多内容
影响因子：
14.9
作者：
Bartlett DW;Davis ME
通讯作者：
Davis ME
影响因子：
64.8
作者：
Soutschek, J;Akinc, A;Vornlocher, HP
通讯作者：
Vornlocher, HP
影响因子：
64.8
作者：
Castanotto, Daniela;Rossi, John J.
通讯作者：
Rossi, John J.
影响因子：
3.6
作者：
RIEHL, R;SCHARTL, M;KOLLINGER, G
通讯作者：
KOLLINGER, G
影响因子：
4.9
作者：
Alvarez, Rene;Elbashir, Sayda;Meyers, Rachel
通讯作者：
Meyers, Rachel