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Systemic peptide-mediated oligonucleotide therapy improves long-term survival in spinal muscular atrophy.

Hammond, SM; Hazell, G; Shabanpoor, F; Saleh, AF; Bowerman, M; Sleigh, JN; Meijboom, KE; Zhou, H; Muntoni, F; Talbot, K; Gait, MJ; Wood, MJA

Systemic peptide-mediated oligonucleotide therapy improves long-term survival in spinal muscular atrophy. Thumbnail


SM Hammond

G Hazell

F Shabanpoor

AF Saleh

JN Sleigh

KE Meijboom

H Zhou

F Muntoni

K Talbot

MJ Gait

MJA Wood


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.

Journal Article Type Article
Acceptance Date Jul 29, 2016
Online Publication Date Sep 12, 2016
Publication Date Sep 27, 2016
Publicly Available Date May 26, 2023
Print ISSN 0027-8424
Electronic ISSN 1091-6490
Publisher National Academy of Sciences
Peer Reviewed Peer Reviewed
Volume 113
Issue 39
Pages 10962 - 10967
Keywords spinal muscular atrophy; survival motor neuron; antisense oligonucleotide; splice switching oligonucleotide; cell-penetrating peptide
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