Pip6-PMO, A New Generation of Peptide-oligonucleotide Conjugates With Improved Cardiac Exon Skipping Activity for DMD Treatment.
Pip6-PMO, A New Generation of Peptide-oligonucleotide Conjugates With Improved Cardiac Exon Skipping Activity for DMD Treatment.
复制标题
DOI：
10.1038/mtna.2012.30
复制
发表时间：
2012-08-14
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
反义寡核苷酸(AOS)是目前治疗Duchenne肌营养不良症(DMD)最有前景的治疗手段。AOS调节dystrophin前mRNA的剪接，从而特异性地恢复dystrophin阅读框架，并产生截短但半功能的dystrophin蛋白。发展这一方法的挑战是相对较差的全身性AO传输，以及受影响的非骨骼肌组织(包括心脏)中Dstrophin校正的低效。我们之前已经报道过令人印象深刻的心脏活动，包括高剪接效率和Dstrophin在单次给药后的恢复，这种富含精氨酸的细胞穿透肽(CPPs)连接到磷二酸吗啉寡核苷酸(PMO)：Pip5e-PMO。然而，人们对这一活动背后的机制知之甚少。在这里，我们报告了涉及单次给药(12.5 mg/kg)的PIP5e-PMO衍生物的研究，连续命名为PIP6-PMOS。这些多肽-PMO包括对Pip5e多肽中心疏水核心的改变，说明对多肽序列的某些改变可以提高其活性；然而，疏水核心内的部分缺失会取消其效率。我们的数据表明，PIP序列的疏水核心对于PMO输送到心脏是关键的，对该区域的特定修饰可以进一步增强活性。这一结果对开发治疗DMD的PMO具有一定的指导意义。
Antisense oligonucleotides (AOs) are currently the most promising therapeutic intervention for Duchenne muscular dystrophy (DMD). AOs modulate dystrophin pre-mRNA splicing, thereby specifically restoring the dystrophin reading frame and generating a truncated but semifunctional dystrophin protein. Challenges in the development of this approach are the relatively poor systemic AO delivery and inefficient dystrophin correction in affected non-skeletal muscle tissues, including the heart. We have previously reported impressive heart activity including high-splicing efficiency and dystrophin restoration following a single administration of an arginine-rich cell-penetrating peptide (CPPs) conjugated to a phosphorodiamidate morpholino oligonucleotide (PMO): Pip5e-PMO. However, the mechanisms underlying this activity are poorly understood. Here, we report studies involving single dose administration (12.5 mg/kg) of derivatives of Pip5e-PMO, consecutively assigned as Pip6-PMOs. These peptide-PMOs comprise alterations to the central hydrophobic core of the Pip5e peptide and illustrate that certain changes to the peptide sequence improves its activity; however, partial deletions within the hydrophobic core abolish its efficiency. Our data indicate that the hydrophobic core of the Pip sequences is critical for PMO delivery to the heart and that specific modifications to this region can enhance activity further. The results have implications for therapeutic PMO development for DMD.
登录
查看更多内容
影响因子：
3
作者：
Butterfield A;Vedagiri V;Lang E;Lawrence C;Wakefield MJ;Isaev A;Huttley GA
通讯作者：
Huttley GA
影响因子：
4.7
作者：
Saleh, Amer F.;Arzumanov, Andrey;Abes, Rachida;Owen, David;Lebleu, Bernard;Gait, Michael J.
通讯作者：
Gait, Michael J.
影响因子：
3.4
作者：
Costas, Jeffrey M.;Nye, David J.;Plochocki, Jeffrey H.
通讯作者：
Plochocki, Jeffrey H.
影响因子：
158.5
作者：
Goemans, Nathalie M.;Tulinius, Mar;van Deutekom, Judith C.
通讯作者：
van Deutekom, Judith C.
影响因子：
10.8
作者：
Jearawiriyapaisarn, Natee;Moulton, Hong M.;Willis, Monte S.
通讯作者：
Willis, Monte S.