Wang Mingxing, Wu Bo, Shah Sapana N, Lu Peijuan, Lu Qilong
McColl-Lockwood Laboratory for Muscular Dystrophy Research, Department of Neurology, Cannon Research Center, Carolinas Medical Center, Charlotte, NC 28203, USA,
Drug Des Devel Ther. 2018 Oct 31;12:3705-3715. doi: 10.2147/DDDT.S179008. eCollection 2018.
Antisense oligonucleotide (ASO)-mediated exon skipping has been feasible and promising approach for treating Duchenne muscular dystrophy (DMD) in preclinical and clinical trials, but its therapeutic applications remain challenges due to inefficient delivery.
We investigated a few Saponins for their potential to improve delivery performance of an antisense 2'-Omethyl phosphorothioate RNA (2'-OMePS) in muscle cells and in dystrophic mice. This study was carried out by evaluating these Saponins' toxicity, cellular uptake, transduction efficiency in vitro, and local delivery in vivo for 2'-OMePS, as well as affinity study between Saponin and 2'-OMePS.
The results showed that these Saponins, especially Digitonin and Tomatine, enhance the delivery of 2'-OMePS with comparable efficiency to Lipofectamine 2k (LF-2k) -mediated delivery in vitro. Significant performance was further observed in mice, up to 10-fold with the Digitonin as compared to 2'-OMePS alone. Cytotoxicity of the Digitonin and Glycyrrhizin was much lower than LF-2k and not clearly detected in vivo under the tested concentrations.
This study potentiates Saponins as delivery vehicle for 2'-OMePS in vivo for treating DMD or other diseases.
在临床前和临床试验中，反义寡核苷酸（ASO）介导的外显子跳跃是治疗杜氏肌营养不良症（DMD）的一种可行且有前景的方法，但由于递送效率低下，其治疗应用仍然面临挑战。
我们研究了几种皂苷在改善反义2'-O-甲基硫代磷酸酯RNA（2'-OMePS）在肌肉细胞和营养不良小鼠中的递送性能方面的潜力。本研究通过评估这些皂苷的毒性、细胞摄取、体外转导效率、2'-OMePS的体内局部递送以及皂苷与2'-OMePS之间的亲和力研究来进行。
结果表明，这些皂苷，尤其是洋地黄皂苷和番茄碱，在体外增强了2'-OMePS的递送，其效率与脂质体2000（LF-2k）介导的递送相当。在小鼠中进一步观察到显著效果，与单独使用2'-OMePS相比，洋地黄皂苷的效果高达10倍。洋地黄皂苷和甘草甜素的细胞毒性远低于LF-2k，在测试浓度下体内未明显检测到。
本研究增强了皂苷作为2'-OMePS体内递送载体治疗DMD或其他疾病的潜力。
