Wang Mingxing, Wu Bo, Shah Sapana N, Lu Peijuan, Lu Qilong
a McColl-Lockwood Laboratory for Muscular Dystrophy Research , Cannon Research Center, Carolinas Medical Center , Charlotte , NC , United States.
Drug Deliv. 2017 Nov;24(1):952-961. doi: 10.1080/10717544.2017.1337827.
Antisense oligonucleotide therapy for Duchenne muscular dystrophy has shown great potential in preclinical and clinical trials, but its therapeutic applications are still limited due to inefficient delivery. In this study, we investigated a few polyquaterniums (PQs) with different size and composition for their potential to improve delivery performance of an antisense phosphorodiamidate morpholino oligomer (PMO) both in vitro and in vivo. The results showed that Luviquat series, especially PQ-1 and PQ-3, promoted the exon-skipping efficiency comparable to Endoporter-mediated PMO delivery in vitro. Significant enhancement in skipping dystrophin exon 23 has also been achieved with PQ-3 up to seven-fold when compared to PMO alone in mdx mice. Cytotoxicity of the PQs was lower than Endoporter and PEI 25 K in vitro and muscle damage not clearly detected in vivo under the tested concentrations. These results together demonstrate that the optimization of PQ in molecular size, composition and distribution of positive charges is the key factor to achieve enhanced PMO exon-skipping efficiency. The higher efficiency and lower toxicity endow polyquaternium series as AO delivery enhancing agents for treating muscular dystrophy and other diseases.
反义寡核苷酸疗法治疗杜氏肌营养不良症在临床前和临床试验中已显示出巨大潜力，但由于递送效率低下，其治疗应用仍然有限。在本研究中，我们研究了几种不同大小和组成的聚季铵盐（PQs）在体外和体内提高反义磷酰胺吗啉代寡聚物（PMO）递送性能的潜力。结果表明，卢维夸特系列，尤其是PQ-1和PQ-3，在体外促进外显子跳跃效率与内转运体介导的PMO递送相当。与mdx小鼠中单独的PMO相比，PQ-3在跳跃肌营养不良蛋白外显子23方面也有显著增强，高达七倍。PQs的细胞毒性在体外低于内转运体和PEI 25K，在测试浓度下体内未明显检测到肌肉损伤。这些结果共同表明，PQ在分子大小、组成和正电荷分布方面的优化是提高PMO外显子跳跃效率的关键因素。更高的效率和更低的毒性使聚季铵盐系列成为治疗肌营养不良症和其他疾病的反义寡核苷酸递送增强剂。
