A morpholino antisense oligonucleotide rescues type I and type III SMA mice

Haiyan Zhou, Narinder Janghra, Karen Anthony, Jennifer Morgan, Francesco Muntoni

Research output: Contribution to journalAbstract

Abstract

The majority of patients affected by Spinal Muscular Atrophy (SMA)
are due to homozygous deletions of Survival Motor Neuron gene 1
(SMN1) which leads to the absence of functional SMN protein,
and results in motor neuron degeneration and muscle weakness.
A second gene, SMN2, encodes a related protein, but a single
nucleotide difference from SMN1 prevents efficient splicing of
exon 7, leading to a truncated transcript and less functional and
unstable protein. Modification of the endogenous SMN2 pre-mRNA
splicing is a promising therapeutic strategy for SMA. Morpholino
antisense oligonucleotides have been successfully used in Duchenne
muscular dystrophy clinical trials and showed satisfactory safety in
preclinical and clinical studies. In this study, we have developed
a new morpholino antisense sequence which targets the intronic
splicing silencer in intron 7 of SMN genes. In vitro data shows
this antisense oligonucleotide induces exon 7 inclusion in SMA
fibroblasts in 100% of the transcript. In vivo validation shows
this morpholino antisense oligonucleotide rescues both type I and
type III SMA mice by systemic delivery in neonatal mice. While
the therapeutic window in severe type I SMA mice is between
post neonatal day 0 to day 3, we show here that Injection of the
morpholino antisense oligonucleotide at post neonatal day 14 to
type III mice still has therapeutic efficacy in delaying tail necrosis,
which suggests a wider therapeutic window in the less severe type
of SMA mice and that rescue of SMN expression in peripheral
tissues still has an effect on SMA phenotype in these mice. Our
study suggests this morpholino antisense oligonucleotide is an
encouraging candidate for future clinical trial in SMA.
Original languageEnglish
JournalNeuromuscular Disorders
Publication statusPublished - 2012

Fingerprint

Spinal Muscular Atrophies of Childhood
Spinal Muscular Atrophy
Morpholinos
Antisense Oligonucleotides
Motor Neurons
Genes
Clinical Trials
Nerve Degeneration
Proteins
Muscle Weakness
Therapeutics
Oligonucleotides
Introns
Tail
Exons
Necrosis
Phenotype
Safety
Injections

Cite this

Zhou, Haiyan ; Janghra, Narinder ; Anthony, Karen ; Morgan, Jennifer ; Muntoni, Francesco. / A morpholino antisense oligonucleotide rescues type I and type III SMA mice. In: Neuromuscular Disorders. 2012.
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title = "A morpholino antisense oligonucleotide rescues type I and type III SMA mice",
abstract = "The majority of patients affected by Spinal Muscular Atrophy (SMA)are due to homozygous deletions of Survival Motor Neuron gene 1(SMN1) which leads to the absence of functional SMN protein,and results in motor neuron degeneration and muscle weakness.A second gene, SMN2, encodes a related protein, but a singlenucleotide difference from SMN1 prevents efficient splicing ofexon 7, leading to a truncated transcript and less functional andunstable protein. Modification of the endogenous SMN2 pre-mRNAsplicing is a promising therapeutic strategy for SMA. Morpholinoantisense oligonucleotides have been successfully used in Duchennemuscular dystrophy clinical trials and showed satisfactory safety inpreclinical and clinical studies. In this study, we have developeda new morpholino antisense sequence which targets the intronicsplicing silencer in intron 7 of SMN genes. In vitro data showsthis antisense oligonucleotide induces exon 7 inclusion in SMAfibroblasts in 100{\%} of the transcript. In vivo validation showsthis morpholino antisense oligonucleotide rescues both type I andtype III SMA mice by systemic delivery in neonatal mice. Whilethe therapeutic window in severe type I SMA mice is betweenpost neonatal day 0 to day 3, we show here that Injection of themorpholino antisense oligonucleotide at post neonatal day 14 totype III mice still has therapeutic efficacy in delaying tail necrosis,which suggests a wider therapeutic window in the less severe typeof SMA mice and that rescue of SMN expression in peripheraltissues still has an effect on SMA phenotype in these mice. Ourstudy suggests this morpholino antisense oligonucleotide is anencouraging candidate for future clinical trial in SMA.",
author = "Haiyan Zhou and Narinder Janghra and Karen Anthony and Jennifer Morgan and Francesco Muntoni",
year = "2012",
language = "English",
journal = "Neuromuscular Disorders",
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A morpholino antisense oligonucleotide rescues type I and type III SMA mice. / Zhou, Haiyan; Janghra, Narinder; Anthony, Karen; Morgan, Jennifer; Muntoni, Francesco.

In: Neuromuscular Disorders, 2012.

Research output: Contribution to journalAbstract

TY - JOUR

T1 - A morpholino antisense oligonucleotide rescues type I and type III SMA mice

AU - Zhou, Haiyan

AU - Janghra, Narinder

AU - Anthony, Karen

AU - Morgan, Jennifer

AU - Muntoni, Francesco

PY - 2012

Y1 - 2012

N2 - The majority of patients affected by Spinal Muscular Atrophy (SMA)are due to homozygous deletions of Survival Motor Neuron gene 1(SMN1) which leads to the absence of functional SMN protein,and results in motor neuron degeneration and muscle weakness.A second gene, SMN2, encodes a related protein, but a singlenucleotide difference from SMN1 prevents efficient splicing ofexon 7, leading to a truncated transcript and less functional andunstable protein. Modification of the endogenous SMN2 pre-mRNAsplicing is a promising therapeutic strategy for SMA. Morpholinoantisense oligonucleotides have been successfully used in Duchennemuscular dystrophy clinical trials and showed satisfactory safety inpreclinical and clinical studies. In this study, we have developeda new morpholino antisense sequence which targets the intronicsplicing silencer in intron 7 of SMN genes. In vitro data showsthis antisense oligonucleotide induces exon 7 inclusion in SMAfibroblasts in 100% of the transcript. In vivo validation showsthis morpholino antisense oligonucleotide rescues both type I andtype III SMA mice by systemic delivery in neonatal mice. Whilethe therapeutic window in severe type I SMA mice is betweenpost neonatal day 0 to day 3, we show here that Injection of themorpholino antisense oligonucleotide at post neonatal day 14 totype III mice still has therapeutic efficacy in delaying tail necrosis,which suggests a wider therapeutic window in the less severe typeof SMA mice and that rescue of SMN expression in peripheraltissues still has an effect on SMA phenotype in these mice. Ourstudy suggests this morpholino antisense oligonucleotide is anencouraging candidate for future clinical trial in SMA.

AB - The majority of patients affected by Spinal Muscular Atrophy (SMA)are due to homozygous deletions of Survival Motor Neuron gene 1(SMN1) which leads to the absence of functional SMN protein,and results in motor neuron degeneration and muscle weakness.A second gene, SMN2, encodes a related protein, but a singlenucleotide difference from SMN1 prevents efficient splicing ofexon 7, leading to a truncated transcript and less functional andunstable protein. Modification of the endogenous SMN2 pre-mRNAsplicing is a promising therapeutic strategy for SMA. Morpholinoantisense oligonucleotides have been successfully used in Duchennemuscular dystrophy clinical trials and showed satisfactory safety inpreclinical and clinical studies. In this study, we have developeda new morpholino antisense sequence which targets the intronicsplicing silencer in intron 7 of SMN genes. In vitro data showsthis antisense oligonucleotide induces exon 7 inclusion in SMAfibroblasts in 100% of the transcript. In vivo validation showsthis morpholino antisense oligonucleotide rescues both type I andtype III SMA mice by systemic delivery in neonatal mice. Whilethe therapeutic window in severe type I SMA mice is betweenpost neonatal day 0 to day 3, we show here that Injection of themorpholino antisense oligonucleotide at post neonatal day 14 totype III mice still has therapeutic efficacy in delaying tail necrosis,which suggests a wider therapeutic window in the less severe typeof SMA mice and that rescue of SMN expression in peripheraltissues still has an effect on SMA phenotype in these mice. Ourstudy suggests this morpholino antisense oligonucleotide is anencouraging candidate for future clinical trial in SMA.

M3 - Abstract

JO - Neuromuscular Disorders

JF - Neuromuscular Disorders

SN - 0960-8966

ER -