Pip5 transduction peptides direct high efficiency oligonucleotide-mediated dystrophin exon skipping in heart and phenotypic correction in mdx mice.
Pip5 transduction peptides direct high efficiency oligonucleotide-mediated dystrophin exon skipping in heart and phenotypic correction in mdx mice.
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DOI：
10.1038/mt.2011.79
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发表时间：
2011-07
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诱导前mRNAs的剪接调节显示出纠正异常疾病转录本和恢复功能蛋白的前景，因此具有治疗潜力。Duchenne肌营养不良症(DMD)是由于突变破坏了DMD基因的开放阅读框架，导致Dstrophin蛋白缺失所致。在最近的两个I期临床试验中，反义寡核苷酸(AO)介导的外显子跳跃已被证明可以恢复MDX小鼠和肌肉注射DMD患者的功能。基于AO的治疗成功的关键将是系统地将AO输送到包括心脏在内的所有受影响组织的能力。在这里，我们报告了一系列转导多肽(PIP5)作为增强全身，特别是心脏递送的AO结合物的鉴定。在mdx小鼠中，先导肽-AO偶联物PIP5E-AO显示了高效的外显子跳跃和Dstrophin的产生，并完全纠正了心脏中异常的DMD转录本，导致心脏中Dstrophin的正常水平超过50%。机理研究表明，PIP5e-PMO活性增强的部分原因是更有效的核传递。因此，PIP5系列衍生物在促进DMD跳过外显子疗法的发展方面具有巨大的潜力，并可能应用于增强其他生物疗法的心脏递送。
Induced splice modulation of pre-mRNAs shows promise to correct aberrant disease transcripts and restore functional protein and thus has therapeutic potential. Duchenne muscular dystrophy (DMD) results from mutations that disrupt the DMD gene open reading frame causing an absence of dystrophin protein. Antisense oligonucleotide (AO)-mediated exon skipping has been shown to restore functional dystrophin in mdx mice and DMD patients treated intramuscularly in two recent Phase I clinical trials. Critical to the therapeutic success of AO-based treatment will be the ability to deliver AOs systemically to all affected tissues including the heart. Here we report identification of a series of transduction peptides (Pip5) as AO conjugates for enhanced systemic and particularly cardiac delivery. One of the lead peptide-AO conjugates, Pip5e-AO, showed highly efficient exon skipping and dystrophin production in mdx mice with complete correction of the aberrant DMD transcript in heart, leading to greater than 50% of the normal level of dystrophin in heart. Mechanistic studies indicated that the enhanced activity of Pip5e-PMO is partly explained by more efficient nuclear delivery. Pip5 series derivatives therefore have significant potential for advancing the development of exon skipping therapies for DMD and may have application for enhanced cardiac delivery of other biotherapeutics.
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影响因子：
5.1
作者：
Wu, B.;Lu, P.;Lu, Q. L.
通讯作者：
Lu, Q. L.
影响因子：
3.5
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Yin, HaiFang;Moulton, Hong M.;Wood, Matthew J. A.
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Wood, Matthew J. A.
影响因子：
5.1
作者：
Aartsma-Rus, A;Kaman, WE;van Deutekom, JCT
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van Deutekom, JCT
影响因子：
3.5
作者：
Gebski, BL;Mann, CJ;Wilton, SD
通讯作者：
Wilton, SD
影响因子：
17.1
作者：
Wood, Matthew J. A.
通讯作者：
Wood, Matthew J. A.