A novel morpholino oligomer targeting ISS-N1 improves rescue of severe spinal muscular atrophy transgenic mice

H. Zhou; N. Janghra; C. Mitrpant; R.L. Dickinson; K. Anthony; L. Price; I.C. Eperon; S.D. Wilton; J. Morgan; F. Muntoni

doi:10.1089/hum.2012.211

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A novel morpholino oligomer targeting ISS-N1 improves rescue of severe spinal muscular atrophy transgenic mice

Journal article

Open access

Peer reviewed

A novel morpholino oligomer targeting ISS-N1 improves rescue of severe spinal muscular atrophy transgenic mice

H. Zhou, N. Janghra, C. Mitrpant, R.L. Dickinson, K. Anthony, L. Price, I.C. Eperon, S.D. Wilton, J. Morgan and F. Muntoni

Human Gene Therapy, Vol.24(3), pp.331-342

2013

DOI: https://doi.org/10.1089/hum.2012.211

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Abstract

In the search for the most efficacious antisense oligonucleotides (AOs) aimed at inducing SMN2 exon 7 inclusion, we systematically assessed three AOs, PMO25 (−10, −34), PMO18 (−10, −27), and PMO20 (−10, −29), complementary to the SMN2 intron 7 splicing silencer (ISS-N1). PMO25 was the most efficacious in augmenting exon 7 inclusion in vitro in spinal muscular atrophy (SMA) patient fibroblasts and in vitro splicing assays. PMO25 and PMO18 were compared further in a mouse model of severe SMA. After a single intracerebroventricular (ICV) injection in neonatal mice, PMO25 increased the life span of severe SMA mice up to 30-fold, with average survival greater by 3-fold compared with PMO18 at a dose of 20 μg/g and 2-fold at 40 μg/g. Exon 7 inclusion was increased in the CNS but not in peripheral tissues. Systemic delivery of PMO25 at birth achieved a similar outcome and produced increased exon 7 inclusion both in the CNS and peripherally. Systemic administration of a 10-μg/g concentration of PMO25 conjugated to an octaguanidine dendrimer (VMO25) increased the life span only 2-fold in neonatal type I SMA mice, although it prevented tail necrosis in mild SMA mice. Higher doses and ICV injection of VMO25 were associated with toxicity. We conclude that (1) the 25-mer AO is more efficient than the 18-mer and 20-mer in modifying SMN2 splicing in vitro; (2) it is more efficient in prolonging survival in SMA mice; and (3) naked Morpholino oligomers are more efficient and safer than the Vivo-Morpholino and have potential for future SMA clinical applications.

Details

Title: A novel morpholino oligomer targeting ISS-N1 improves rescue of severe spinal muscular atrophy transgenic mice
Authors/Creators: H. Zhou (Author/Creator)
N. Janghra (Author/Creator)
C. Mitrpant (Author/Creator)
R.L. Dickinson (Author/Creator)
K. Anthony (Author/Creator)
L. Price (Author/Creator)
I.C. Eperon (Author/Creator)
S.D. Wilton (Author/Creator)
J. Morgan (Author/Creator)
F. Muntoni (Author/Creator)
Publication Details: Human Gene Therapy, Vol.24(3), pp.331-342
Publisher: Mary Ann Liebert Inc.
Identifiers: 991005542172307891
Copyright: ©2012 Mary Ann Liebert, Inc
Murdoch Affiliation: Murdoch University
Language: English
Resource Type: Journal article

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.255 Musculoskeletal Disorders; 1.255.2204 Spinal Muscular Atrophy
Web Of Science research areas: Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental
ESI research areas: Molecular Biology & Genetics