Re: R&D Recent Article Abstract - anti-sense therapy

[Guest guest]

Lots of scientific mumbo-jumbo in the article - which

I have a vague understanding of some of the various

references - but importantly the abstract notes

" strong potential for antisense-mediated therapy of

SMA " - Mitch

1: RNA Biol. 2007 Jun 4;4(1) [Epub ahead of print]

Evolving Concepts on Human SMN Pre-mRNA Splicing.

Singh RN.

SMN1 and SMN2 represent two nearly identical

copies of the survival motor neuron gene in humans.

Deletion of SMN1 coupled with the inability of SMN2 to

compensate for the loss of SMN1 leads to spinal

muscular atrophy (SMA), a leading genetic cause of

infant mortality. SMN2 holds the promise for cure of

SMA if skipping of exon 7 during pre-mRNA splicing of

SMN2 could be prevented. Previous reports have shown

that a C to Tmutation at the 6(th) position of exon 7

(C6U substitution in the transcript) is the primary

cause of SMN2 exon 7 skipping. Cumulative evidence

suggests that C6U abrogates an enhancer associated

with SF2/ASF, as well as, creates a silencer

associated with hnRNP A1. There is also evidence to

suggest that C6U creates an extended inhibitory

context (Exinct). Recently, an intronic hnRNP A1

motif, which is not conserved between two human SMN

genes, has been implicated in skipping of SMN2 exon 7.

However, mechanism by which two SMN2-specific hnRNP A1

motifs interact is not known. Systematic approaches

including site-specific mutations, in vivo selections,

RNA structure probing and antisense oligonucleotide

microwalks have revealed additional cis-elements in

exon 7 as well as in flanking intronic sequences. A

unique intronic splicing silencer (ISS-N1) has emerged

as an effective target for correction of SMN2 exon 7

splicing by short antisense oligonucleotides (ASOs).

Low nanomolar concentrations of ASOs against ISS-N1

fully restored SMN2 exon 7 inclusion and increased

levels of SMN in SMA patient cells. Such a robust

antisense response could be due to accessibility of

the target as well as the complete nullification of a

strong inhibitory impact rendered by ISS-N1.

Bifunctional oligonucelotides with capability to

recruit stimulatory splicing factors in the vicinity

of weak splice sites of exon 7 have also shown promise

for correction of SMN2 exon 7 splicing. Considering an

antisense-based strategy confers a unique advantage of

sequence specificity, availability of many target

worthy cis-elements holds strong potential for

antisense-mediated therapy of SMA.

PMID: 17592254 [PubMed - as supplied by publisher]

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