Hammond, SM and Hazell, G and Shabanpoor, F and Saleh, AF and Bowerman, M and Sleigh, JN and Meijboom, KE and Zhou, H and Muntoni, F and Talbot, K and Gait, MJ and Wood, MJA (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). 10962 - 10967. ISSN 0027-8424

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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.

Item Type: Article
Uncontrolled Keywords: spinal muscular atrophy; survival motor neuron; antisense oligonucleotide; splice switching oligonucleotide; cell-penetrating peptide
Subjects: Q Science > Q Science (General)
R Medicine > R Medicine (General)
R Medicine > RC Internal medicine > RC925 Diseases of the musculoskeletal system
Divisions: Faculty of Medicine and Health Sciences > Institute for Science and Technology in Medicine
Related URLs:
Depositing User: Symplectic
Date Deposited: 03 Nov 2017 12:04
Last Modified: 03 Nov 2017 12:04
URI: http://eprints.keele.ac.uk/id/eprint/4176

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