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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; ... Wood, MJ; + view all (2016) Systemic peptide-mediated oligonucleotide therapy improves long-term survival in spinal muscular atrophy. Proceedings of the National Academy of Sciences of the United States of America , 113 (39) pp. 10962-10967. 10.1073/pnas.1605731113. Green open access

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Abstract

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.

Type: Article
Title: Systemic peptide-mediated oligonucleotide therapy improves long-term survival in spinal muscular atrophy
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1073/pnas.1605731113
Publisher version: http://dx.doi.org/10.1073/pnas.1605731113
Language: English
Additional information: Copyright © 2016 National Academy of Sciences. This is the accepted manuscript version of this article; the published PNAS open access version can be found on the journal website at http://dx.doi.org/10.1073/pnas.1605731113
Keywords: antisense oligonucleotide, cell-penetrating peptide, spinal muscular atrophy, splice switching oligonucleotide, survival motor neuron
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Neurosciences Dept
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept
URI: https://discovery.ucl.ac.uk/id/eprint/1516754
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