Development of Targeted siRNA Nanocomplexes to Prevent Fibrosis in Experimental Glaucoma Filtration Surgery.
Development of Targeted siRNA Nanocomplexes to Prevent Fibrosis in Experimental Glaucoma Filtration Surgery.
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DOI：
10.1016/j.ymthe.2018.09.004
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发表时间：
2018-12-05
期刊：
影响因子：
--
通讯作者：
Yu-Wai-Man C
中科院分区：
文献类型：
--
作者：
Fernando O;Tagalakis AD;Awwad S;Brocchini S;Khaw PT;Hart SL;Yu-Wai-Man C
由双链小干扰RNA（siRNA）分子诱导的RNAi作为一种天然存在的高特异性沉默基因表达的方法受到了极大的关注。肌红蛋白相关转录因子/血清反应因子（MRTF/SRF）通路是细胞骨架基因表达的主要调节因子，因此，代表了预防纤维化的有希望的靶点。实施siRNA疗法的一个主要障碍是递送方法，因此，我们已经优化了含有MRTF-B siRNA的脂质肽siRNA（LPR）纳米颗粒作为预防结膜纤维化的靶向方法。我们在人结膜成纤维细胞中测试了15种具有不同脂质组成、表面电荷和靶向或非靶向肽的LPR纳米颗粒制剂。在体外，与非靶向制剂相比，具有靶向肽Y（LYR）的DOTMA/DOPE脂质的LPR制剂在MRTF-B基因沉默方面是最有效的并且是无细胞毒性的。在体内，在青光眼滤过手术的临床前兔模型中，结膜下施用含有MRTF-B siRNA的LYR纳米颗粒使滤过泡存活率加倍。此外，MRTF-B LYR纳米颗粒使兔结膜组织中的MRTF-B mRNA降低了29.6%，这导致结膜瘢痕形成显著减少，而没有不良副作用。LYR介导的siRNA递送显示出增加滤过泡存活和预防青光眼滤过手术后结膜纤维化的有希望的结果。由双链小干扰RNA（siRNA）诱导的RNAi是一种天然存在的高特异性沉默基因表达的方法。Yu-Wai-Man及其同事在青光眼滤过手术的临床前模型中显示，脂质肽siRNA（LPR）纳米颗粒显著增加滤过泡存活率并预防结膜纤维化。
RNAi induced by double-stranded small interfering RNA (siRNA) molecules has attracted great attention as a naturally occurring approach to silence gene expression with high specificity. The myocardin-related transcription factor/serum response factor (MRTF/SRF) pathway is a master regulator of cytoskeletal gene expression and, thus, represents a promising target to prevent fibrosis. A major hurdle to implementing siRNA therapies is the method of delivery, and we have, thus, optimized lipid-peptide-siRNA (LPR) nanoparticles containing MRTF-B siRNAs as a targeted approach to prevent conjunctival fibrosis. We tested 15 LPR nanoparticle formulations with different lipid compositions, surface charges, and targeting or non-targeting peptides in human conjunctival fibroblasts. In vitro, the LPR formulation of the DOTMA/DOPE lipid with the targeting peptide Y (LYR) was the most efficient in MRTF-B gene silencing and non-cytotoxic compared to the non-targeting formulation. In vivo, subconjunctival administration of LYR nanoparticles containing MRTF-B siRNAs doubled bleb survival in a pre-clinical rabbit model of glaucoma filtration surgery. Furthermore, MRTF-B LYR nanoparticles reduced the MRTF-B mRNA by 29.6% in rabbit conjunctival tissues, which led to significantly decreased conjunctival scarring with no adverse side effects. LYR-mediated delivery of siRNA shows promising results to increase bleb survival and to prevent conjunctival fibrosis after glaucoma filtration surgery. RNAi induced by double-stranded, small interfering RNA (siRNA) is a naturally occurring approach to silence gene expression with high specificity. Yu-Wai-Man and colleagues show that lipid-peptide-siRNA (LPR) nanoparticles significantly increase bleb survival and prevent conjunctival fibrosis in a pre-clinical model of glaucoma filtration surgery.
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DOI：
10.1038/nrm2890
发表时间：
2010-05
期刊：
Nature reviews. Molecular cell biology
影响因子：
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作者：
通讯作者：
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影响因子：
4.8
作者：
LIU, Y;LIGGITT, D;DEBS, R
通讯作者：
DEBS, R
影响因子：
12.4
作者：
Draz MS;Fang BA;Zhang P;Hu Z;Gu S;Weng KC;Gray JW;Chen FF
通讯作者：
Chen FF
影响因子：
5.1
作者：
通讯作者：
--
影响因子：
12.4
作者：
Martinez, Tamara;Victoria Gonzalez, Maria;Isabel Jimenez, Ana
通讯作者：
Isabel Jimenez, Ana