Identification of a Peptide for Systemic Brain Delivery of a Morpholino Oligonucleotide in Mouse Models of Spinal Muscular Atrophy.
Identification of a Peptide for Systemic Brain Delivery of a Morpholino Oligonucleotide in Mouse Models of Spinal Muscular Atrophy.
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DOI：
10.1089/nat.2016.0652
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发表时间：
2017-06
影响因子：
4
通讯作者：
Gait MJ
中科院分区：
文献类型：
--
作者：
Shabanpoor F;Hammond SM;Abendroth F;Hazell G;Wood MJA;Gait MJ
剪接转换反义寡核苷酸是神经肌肉疾病的新兴治疗方法，目前正在进行临床试验的几种剪接转换寡核苷酸（SSO），如杜氏肌营养不良症（DMD）和脊髓性肌萎缩症（SMA）。然而，全身递送的反义治疗剂的开发受到不良的组织渗透和细胞摄取的阻碍，包括穿过血脑屏障（BBB）到达中枢神经系统（CNS）中的靶标。对于SMA应用，我们已经研究了各种BBB-交叉肽用于CNS递送靶向运动神经元存活2（SMN 2）外显子7包含的剪接转换磷酸二酰胺吗啉代寡核苷酸（PMO）的能力。我们鉴定了一种众所周知的ApoE（141-150）肽的分支衍生物，其作为PMO偶联物能够在全身给药后在CNS中包含外显子，导致全长SMN 2转录物水平增加。用这种肽-PMO（P-PMO）缀合物治疗新生SMA小鼠导致平均寿命的显著增加以及体重、肌肉力量和翻正反射的增加。用这种新发现的P-PMO对成年SMA小鼠进行全身给药也导致CNS和外周组织中SMN 2前信使RNA（mRNA）外显子包涵体水平小幅但显著增加。这项工作为选择新肽范例的能力提供了原理证明，通过使用基于肽的递送平台来治疗可能扩展到其他神经肌肉和神经退行性疾病的SMA，以增强PMO SSO的中枢神经系统递送和活性。
Splice-switching antisense oligonucleotides are emerging treatments for neuromuscular diseases, with several splice-switching oligonucleotides (SSOs) currently undergoing clinical trials such as for Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA). However, the development of systemically delivered antisense therapeutics has been hampered by poor tissue penetration and cellular uptake, including crossing of the blood–brain barrier (BBB) to reach targets in the central nervous system (CNS). For SMA application, we have investigated the ability of various BBB-crossing peptides for CNS delivery of a splice-switching phosphorodiamidate morpholino oligonucleotide (PMO) targeting survival motor neuron 2 (SMN2) exon 7 inclusion. We identified a branched derivative of the well-known ApoE (141–150) peptide, which as a PMO conjugate was capable of exon inclusion in the CNS following systemic administration, leading to an increase in the level of full-length SMN2 transcript. Treatment of newborn SMA mice with this peptide-PMO (P-PMO) conjugate resulted in a significant increase in the average lifespan and gains in weight, muscle strength, and righting reflexes. Systemic treatment of adult SMA mice with this newly identified P-PMO also resulted in small but significant increases in the levels of SMN2 pre-messenger RNA (mRNA) exon inclusion in the CNS and peripheral tissues. This work provides proof of principle for the ability to select new peptide paradigms to enhance CNS delivery and activity of a PMO SSO through use of a peptide-based delivery platform for the treatment of SMA potentially extending to other neuromuscular and neurodegenerative diseases.