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首页> 外文期刊>Nucleic Acid Therapeutics >Approaches for Systemic Delivery of Dystrophin Antisense Peptide Nucleic Acid in the mdx Mouse Model
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Approaches for Systemic Delivery of Dystrophin Antisense Peptide Nucleic Acid in the mdx Mouse Model

机译：MDX小鼠模型中肌营养蛋白反义肽核酸的全身递送方法

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Antisense-mediated exon skipping constitutes a promising new modality for treatment of Duchenne Muscular Dystrophy (DMD), which is caused by gene mutations that typically introduce a translation stop codon in the dystrophin gene, thereby abolishing production of functional dystrophin protein. The exon removal can restore translation to produce a shortened, but still partially functional dystrophin protein. Peptide nucleic acid (PNA) as a potential antisense drug has previously been shown to restore the expression of functional dystrophin by splice modulation in the mdx mouse model of DMD. In this study, we compare systemic administration of a 20-mer splice switching antisense PNA oligomer through intravenous (i.v.) and subcutaneous (s.c.) routes in the mdx mice. Furthermore, the effect ofin situforming depot technology (BEPO(R)) and PNA-oligonucleotide formulation was studied.In vivofluorescence imaging analysis showed fast renal/bladder excretion of the PNA (t(1/2)similar to 20 min) for i.v. administration, while s.c. administration showed a two to three times slower excretion. The release from the BEPO depot exhibited biphasic kinetics with a slow release (t(1/2)similar to 10 days) of 50% of the dose. In all cases, some accumulation in kidneys and liver could be detected. Formulation of PNA as a duplex hybridization complex with a complementary phosphorothioate oligonucleotide increased the solubility of the PNA. However, none of these alternative administration methods resulted in significantly improved antisense activity. Therefore, either more sophisticated formulations such as designed nanoparticles or conjugation to delivery ligands must be utilized to improve both pharmacokinetics as well as tissue targeting and availability. On the other hand, the results show that s.c. and BEPO depot administration of PNA are feasible and allow easier, higher, and less frequent dosing, as well as more controlled release, which can be exploited both for animal model studies as well as eventually in the clinic in terms of dosing optimization.
机译：反义介导的外显子跳跃是治疗Duchenne型肌营养不良症（DMD）的一种有前途的新方法，DMD是由通常在肌营养不良蛋白基因中引入翻译终止密码子的基因突变引起的，从而消除了功能性肌营养不良蛋白的产生。外显子的去除可以恢复翻译，产生一种缩短但仍具有部分功能的肌营养不良蛋白。在mdx小鼠DMD模型中，肽核酸（PNA）作为一种潜在的反义药物已被证明通过剪接调节恢复功能性肌营养不良蛋白的表达。在这项研究中，我们比较了在mdx小鼠中通过静脉（i.v.）和皮下（s.c.）途径全身给药20-聚体剪接开关反义PNA寡聚体。此外，还研究了原位成型仓库技术（BEPO（R））和PNA寡核苷酸配方的效果。活体荧光成像分析显示，静脉注射给药后，PNA的肾/膀胱排泄速度快（t（1/2）类似于20分钟），而皮下注射给药后，PNA的排泄速度慢了两到三倍。从BEPO仓库的释放表现出双相动力学，缓慢释放（t（1/2）类似于10天）为剂量的50%。在所有病例中，都可以检测到肾脏和肝脏中的一些堆积物。PNA与互补的硫代磷酸寡核苷酸形成双重杂交复合物，增加了PNA的溶解性。然而，这些替代给药方法均未显著提高反义活性。因此，必须利用更复杂的配方，如设计的纳米颗粒或与递送配体的结合来改善药代动力学以及组织靶向性和可用性。另一方面，结果表明，s.c.和BEPO仓库给药PNA是可行的，并且允许更容易、更高和更少频率的给药，以及更多的控制释放，这可以用于动物模型研究，最终也可以用于临床给药优化。

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