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

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.