Systemic peptide-mediated oligonucleotide therapy improves long-term survival in spinal muscular atrophy
Systemic peptide-mediated oligonucleotide therapy improves long-term survival in spinal muscular atrophy
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DOI：
10.1073/pnas.1605731113
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发表时间：
2016-09-27
影响因子：
11.1
通讯作者：
Wood, Matthew J. A.
中科院分区：
文献类型：
--
作者：
Hammond, Suzan M.;Hazell, Gareth;Wood, Matthew J. A.
反义寡核苷酸治疗的发展是神经肌肉疾病（如脊髓性肌萎缩症（SMA））矫正治疗的重要进展。由于难以将单链寡核苷酸递送至CNS，目前的方法已限于使用侵入性鞘内单链寡核苷酸递送。在这里，我们报告了一种先进的肽寡核苷酸，Pip 6a-吗啉代磷酰二胺寡聚体（PMO），这表明在严重的SMA小鼠的中枢神经系统和外周组织的有效性后，全身给药。SMA是由普遍表达的运动神经元存活（SMN）蛋白水平降低引起的，这是由于SMN 1基因的功能缺失突变所致。治疗性剪接转换寡核苷酸（SSO）调节几乎相同的SMN 2基因的外显子7剪接，以产生功能性SMN蛋白。Pip 6a-PMO在外周和CNS组织中以高效率产生SMN表达，从而在比标准裸SSO所需的剂量低一个数量级的剂量下产生深刻的表型校正。生存期从12天显著延长至平均456天，神经肌肉接头形态改善，脊髓程序性细胞死亡相关转录物下调，循环胰岛素样生长因子1正常化。靶向外周组织以及CNS组织的Pip 6a-PMO的有效全身功效证明了肽-PMO疗法用于SMA的高临床潜力。
The development of antisense oligonucleotide therapy is an important advance in the identification of corrective therapy for neuromuscular diseases, such as spinal muscular atrophy (SMA). Because of difficulties of delivering single-stranded oligonucleotides to the CNS, current approaches have been restricted to using invasive intrathecal single-stranded oligonucleotide delivery. Here, we report an advanced peptide-oligonucleotide, Pip6a-morpholino phosphorodiamidate oligomer (PMO), which demonstrates potent efficacy in both the CNS and peripheral tissues in severe SMA mice following systemic administration. SMA results from reduced levels of the ubiquitously expressed survival motor neuron (SMN) protein because of loss-of-function mutations in the SMN1 gene. Therapeutic splice-switching oligonucleotides (SSOs) modulate exon 7 splicing of the nearly identical SMN2 gene to generate functional SMN protein. Pip6a-PMO yields SMN expression at high efficiency in peripheral and CNS tissues, resulting in profound phenotypic correction at doses an order-of-magnitude lower than required by standard naked SSOs. Survival is dramatically extended from 12 d to a mean of 456 d, with improvement in neuromuscular junction morphology, down-regulation of transcripts related to programmed cell death in the spinal cord, and normalization of circulating insulin-like growth factor 1. The potent systemic efficacy of Pip6a-PMO, targeting both peripheral as well as CNS tissues, demonstrates the high clinical potential of peptide-PMO therapy for SMA.