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首页> 外文期刊>Nucleic Acid Therapeutics >Chitosan-Shelled Nanobubbles Irreversibly Encapsulate Morpholino Conjugate Antisense Oligonucleotides and Are Ineffective for Phosphorodiamidate Morpholino-Mediated Gene Silencing ofDUX4
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Chitosan-Shelled Nanobubbles Irreversibly Encapsulate Morpholino Conjugate Antisense Oligonucleotides and Are Ineffective for Phosphorodiamidate Morpholino-Mediated Gene Silencing ofDUX4

机译：壳聚糖壳的纳米泡不可逆转地封装了吗啉缀合物反义寡核苷酸，对磷膦酸酯的吗啉代介导的基因沉默是无效的

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Orphan drugs, including antisense oligonucleotides (AONs), siRNAs/miRNAs, Cas9 nuclease, and recombinant genes, have recently been made available for rare diseases. However, the main bottleneck for these new therapies is delivery. Drugs/synthetic genes need to reach the affected tissues with minimal off-target effects and immune reactions. AON molecules are currently delivered as backboned naked compounds or via viral vectors. Nanocarriers are considered promising vehicles, able to improve drug distribution by organ targeting and limiting safety issues. We tested perfluoropentane-based nanobubbles (NBs) as vehicles for loading phosphorodiamidate morpholino (PMO) AON to suppress DUX4 expression in a facioscapulohumeral muscular dystrophy cell model.In vitrocell-free analysis demonstrated a good loading capacity of PMO into NBs, while experiments in cell cultures showed lack of therapeutic effect since expression of DUX4 and its targets remained unmodified. We conclude that these types of chitosan-shelled NBs do not release PMO-AON and are therefore not ideal for PMO AON-related therapies.
机译：孤儿药物，包括反义寡核苷酸（AON）、siRNA/miRNA、Cas9核酸酶和重组基因，最近已被用于治疗罕见疾病。然而，这些新疗法的主要瓶颈是交付。药物/合成基因需要以最小的脱靶效应和免疫反应到达受影响的组织。目前，AON分子是以骨架裸化合物或通过病毒载体传递的。纳米载体被认为是很有前途的载体，能够通过器官靶向和限制安全问题来改善药物分布。我们在面肩肱型肌营养不良细胞模型中测试了全氟戊烷基纳米气泡（NBs）作为载药磷酸二酰胺吗啉（PMO）AON抑制DUX4表达的载体。体外无细胞分析显示PMO对NBs具有良好的负载能力，而细胞培养实验显示，由于DUX4及其靶点的表达未发生改变，因此缺乏治疗效果。我们得出结论，这些类型的壳聚糖壳NBs不会释放PMO-AON，因此不适合PMO-AON相关疗法。

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