Peptide Nucleic Acid Promotes Systemic Dystrophin Expression and Functional Rescue in Dystrophin-deficient mdx Mice.
Peptide Nucleic Acid Promotes Systemic Dystrophin Expression and Functional Rescue in Dystrophin-deficient mdx Mice.
复制标题
肽核酸促进肌营养不良蛋白缺陷 mdx 小鼠的全身肌营养不良蛋白表达和功能拯救。
DOI：
10.1038/mtna.2015.27
复制
发表时间：
2015-10-06
期刊：
影响因子：
--
通讯作者：
Yin H
中科院分区：
文献类型：
--
作者：
Gao X;Shen X;Dong X;Ran N;Han G;Cao L;Gu B;Yin H
反义寡核苷酸（AO）介导的外显子跳跃疗法对杜氏肌营养不良症（DMD）患者显示出巨大的希望。然而，最近在3期临床试验中的AO候选药物drisapersen的失败突出了探索DMD的其他有效AO化学的重要性。先前，我们证明了肽核酸（PNA）AO在肌内恢复肌营养不良蛋白缺陷型mdx小鼠中肌营养不良蛋白表达的可观生物活性。在这里，我们进一步探索PNA AO在mdx小鼠中介导外显子跳跃的系统潜力和可行性，因为仍然缺乏全面的系统评价。PNA AO的全身递送导致全身外周肌肉中治疗水平的肌营养不良蛋白表达，并改善mdx小鼠中的营养不良病理学，而没有任何可检测的毒性。在腓肠肌中实现了高达40%的肌营养不良蛋白恢复，在其他骨骼肌中达到较小程度，心脏中没有肌营养不良蛋白。值得注意的是，在相同的给药方案下，在PNA AO和磷酰二胺吗啉代寡聚体（3期临床试验中的DMD AO化学）之间获得了相当的全身活性。总的来说，我们的数据表明，PNA对于DMD外显子跳跃治疗是可行的，其中20聚体显示出活性、溶解度和安全性的最佳组合，并且进一步修饰以增加PNA水溶性可以实现更长、更有效的治疗而没有相关的毒性。
Antisense oligonucleotide (AO)-mediated exon-skipping therapeutics shows great promise for Duchenne muscular dystrophy (DMD) patients. However, recent failure with drisapersen, an AO candidate drug in phase 3 trial, highlights the importance of exploring other effective AO chemistries for DMD. Previously, we demonstrated the appreciable biological activity of peptide nucleic acid (PNA) AOs in restoring dystrophin expression in dystrophin-deficient mdx mice intramuscularly. Here, we further explore the systemic potential and feasibility of PNA AOs in mediating exon skipping in mdx mice as a comprehensive systemic evaluation remains lacking. Systemic delivery of PNA AOs resulted in therapeutic level of dystrophin expression in body-wide peripheral muscles and improved dystrophic pathology in mdx mice without any detectable toxicity. Up to 40% of dystrophin restoration was achieved in gastrocnemius, to a less extent with other skeletal muscles, with no dystrophin in heart. Notably, comparable systemic activity was obtained between PNA AOs and phosphorodiamidate morpholino oligomer, a DMD AO chemistry in phase 3 clinical trial, under an identical dosing regimen. Overall, our data demonstrate that PNA is viable for DMD exon-skipping therapeutics with 20 mer showing the best combination of activity, solubility, and safety and further modifications to increase PNA aqueous solubility can enable longer, more effective therapeutics without the associated toxicity.