通过压缩 DNA 纳米颗粒将基因递送至有丝分裂和有丝分裂后光感受器，可改善视网膜色素变性小鼠模型的表型。
Gene delivery to mitotic and postmitotic photoreceptors via compacted DNA nanoparticles results in improved phenotype in a mouse model of retinitis pigmentosa.
机构信息
Department of Cell Biology, University of Oklahoma Health Sciences Center, 940 Stanton L. Young Blvd., BMSB 781, Oklahoma City, OK 73104, USA.
出版信息
FASEB J. 2010 Apr;24(4):1178-91. doi: 10.1096/fj.09-139147. Epub 2009 Dec 1.
The purpose of the present study was to test the therapeutic efficiency and safety of compacted-DNA nanoparticle-mediated gene delivery into the subretinal space of a juvenile mouse model of retinitis pigmentosa. Nanoparticles containing the mouse opsin promoter and wild-type mouse Rds gene were injected subretinally into mice carrying a haploinsufficiency mutation in the retinal degeneration slow (rds(+ or -)) gene at postnatal day (P)5 and 22. Control mice were either injected with saline, injected with uncompacted naked plasmid DNA carrying the Rds gene, or remained untreated. Rds mRNA levels peaked at postinjection day 2 to 7 (PI-2 to PI-7) for P5 injections, stabilized at levels 2-fold higher than in uninjected controls for both P5 and P22 injections, and remained elevated at the latest time point examined (PI-120). Rod function (measured by electroretinography) showed modest but statistically significant improvement compared with controls after both P5 and P22 injections. Cone function in nanoparticle-injected eyes reached wild-type levels for both ages of injections, indicating full prevention of cone degeneration. Ultrastructural examination at PI-120 revealed significant improvement in outer segment structures in P5 nanoparticle-injected eyes, while P22 injection had a modest structural improvement. There was no evidence of macrophage activation or induction of IL-6 or TNF-alpha mRNA in P5 or P22 nanoparticle-dosed eyes at either PI-2 or PI-30. Thus, compacted-DNA nanoparticles can efficiently and safely drive gene expression in both mitotic and postmitotic photoreceptors and retard degeneration in this model. These findings, using a clinically relevant treatment paradigm, illustrate the potential for application of nanoparticle-based gene replacement therapy for treatment of human retinal degenerations.-Cai, X., Conley, S. M., Nash, Z., Fliesler, S. J., Cooper, M. J., Naash, M. I. Gene delivery to mitotic and postmitotic photoreceptors via compacted DNA nanoparticles results in improved phenotype in a mouse model of retinitis pigmentosa.
本研究的目的是测试致密 DNA 纳米颗粒介导的基因递送至视网膜色素变性幼年小鼠模型的视网膜下腔的治疗效率和安全性。将含有小鼠视蛋白启动子和野生型小鼠 Rds 基因的纳米颗粒在出生后第 5 天（P5）和 22 天（P22）向携带视网膜变性缓慢（rds(+或-))基因单倍不足突变的小鼠的视网膜下腔注射。对照小鼠要么注射生理盐水，要么注射携带 Rds 基因的未致密裸质粒 DNA，要么不治疗。rds mRNA 水平在 P5 注射后的注射后第 2 至 7 天（PI-2 至 PI-7）达到峰值，在 P5 和 P22 注射时稳定在比未注射对照高 2 倍的水平，并在检测到的最新时间点（PI-120）升高。与对照相比，在 P5 和 P22 注射后，杆状功能（通过视网膜电图测量）均略有但具有统计学意义的改善。在 P5 和 P22 两种年龄的注射中，纳米颗粒注射眼的锥状功能均达到野生型水平，表明完全预防了锥状细胞变性。PI-120 的超微结构检查显示，在 P5 纳米颗粒注射眼的外节结构有显著改善，而 P22 注射则有适度的结构改善。在 P5 或 P22 纳米颗粒给药的眼睛中，在 PI-2 或 PI-30 时，均未观察到巨噬细胞激活或白细胞介素-6 或肿瘤坏死因子-α mRNA 的诱导。因此，致密 DNA 纳米颗粒可以有效地、安全地驱动有丝分裂和有丝分裂后光感受器中的基因表达，并延缓该模型中的变性。这些发现使用了一种临床相关的治疗范例，说明了基于纳米颗粒的基因替代疗法在治疗人类视网膜变性方面的应用潜力。-蔡，X.，康利，S. M.，纳什，Z.，弗利泽尔，S. J.，库珀，M. J.，纳沙，M. I. 通过致密 DNA 纳米颗粒将基因递送至有丝分裂和有丝分裂后光感受器，可改善视网膜色素变性小鼠模型的表型。
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