Big win possible for Ionis/Biogen antisense drug in muscular atrophy

@article{Garber2016BigWP,
  title={Big win possible for Ionis/Biogen antisense drug in muscular atrophy},
  author={Ken Garber},
  journal={Nature Biotechnology},
  year={2016},
  volume={34},
  pages={1002-1003}
}
  • K. Garber
  • Published 11 October 2016
  • Biology
  • Nature Biotechnology
VOLUME 34 NUMBER 10 OCTOBER 2016 NATURE BIOTECHNOLOGY as potently. “An important and lucky observation,” says Krainer. “We didn’t expect it, and we didn’t initially understand it.” Upon publication of the finding, Ionis contacted Krainer and began collaborating with him (Nat. Struct. Biol. 10, 120–125, 2003). Ionis brought its antisense technology to the table. The company’s 2ʹ-O-methoxyethyl (2ʹMOE) phosphorothioate chemistry, with sulfur substituting for one of the non-bridging oxygen atoms… 

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References

SHOWING 1-8 OF 8 REFERENCES

SMN2 splice modulators enhance U1-pre-mRNA association and rescue SMA mice.

TLDR
A potent, orally active, small-molecule enhancer of SMN2 splicing that elevates full-length SMN protein and extends survival in a severe SMA mouse model is described, demonstrating the feasibility of small molecule-mediated, sequence-selective splice modulation and the potential for leveraging this strategy in other splicing diseases.

SMN2 splicing modifiers improve motor function and longevity in mice with spinal muscular atrophy

TLDR
Small molecules that alter splicing of a specific messenger RNA have beneficial effects in a model of a motor neuron disease and selective SMN2 splicing modifiers may have therapeutic potential for patients with SMA.

A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy.

TLDR
The failure of SMN2 to fully compensate for SMN1 and protect from SMA is due to a nucleotide exchange (C/T) that attenuates activity of an exonic enhancer.

Results from a phase 1 study of nusinersen (ISIS-SMNRx) in children with spinal muscular atrophy

TLDR
This study provides Class IV evidence that in children with SMA, intrathecal nusinersen is not associated with safety or tolerability concerns, and support continued development of nusineren for treatment of SMA.

Peripheral SMN restoration is essential for long-term rescue of a severe SMA mouse model

TLDR
It is suggested that the liver is important in SMA pathogenesis, underscoring the importance of SMN in peripheral tissues, and the efficacy of a promising drug candidate is demonstrated.

Correction of disease-associated exon skipping by synthetic exon-specific activators

TLDR
Small chimeric effectors comprising a minimal synthetic RS domain covalently linked to an antisense moiety that targets an exon by Watson-Crick base pairing can mimic the functions of SR proteins and restore wild type splicing when directed to defective BRCA1 or SMN2 pre-mRNA transcripts.