Antisense oligonucleotides: the next frontier for treatment of neurological disorders

@article{Rinaldi2018AntisenseOT,
  title={Antisense oligonucleotides: the next frontier for treatment of neurological disorders},
  author={Carlo Rinaldi and Matthew J. A. Wood},
  journal={Nature Reviews Neurology},
  year={2018},
  volume={14},
  pages={9-21}
}
Antisense oligonucleotides (ASOs) were first discovered to influence RNA processing and modulate protein expression over two decades ago; however, progress translating these agents into the clinic has been hampered by inadequate target engagement, insufficient biological activity, and off-target toxic effects. Over the years, novel chemical modifications of ASOs have been employed to address these issues. These modifications, in combination with elucidation of the mechanism of action of ASOs… 

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References

SHOWING 1-10 OF 211 REFERENCES

Antisense Oligonucleotides: Treating Neurodegeneration at the Level of RNA

Many of the more commonly used antisense oligonucleotides (ASOs) chemistries are discussed, as well as the different mechanisms of action that can result from these specific chemical modifications.

Nanoparticle delivery of antisense oligonucleotides and their application in the exon skipping strategy for Duchenne muscular dystrophy.

This review describes the recent progress in AON conjugation with natural and synthetic delivery systems, and provides an overview of the efficacy of NP-AON complexes as an exon-skipping treatment for Duchenne muscular dystrophy.

Targeting RNA to treat neuromuscular disease

Recent advances in the development of antisense oligonucleotides and other promising novel approaches, including the induction of readthrough nonsense mutations are reviewed.

Antisense oligonucleotide therapy for neurodegenerative disease.

Treatment initiated near onset significantly slowed disease progression in a model of amyotrophic lateral sclerosis caused by a mutation in SOD1, suggesting that direct delivery of antisense oligonucleotides could be an effective, dosage-regulatable means of treating neurodegenerative diseases, including ALS, where appropriate target proteins are known.

Clinical pharmacokinetics of second generation antisense oligonucleotides

A limited but growing database on chronic dosing of second generation ASOs, across various patient and special populations, and also with non-systemic local delivery approaches, will help further characterize the clinical PK properties of these compounds and better quantify the extent and sources of any observed PK variability and potential impact on clinical response.

Systemic peptide-mediated oligonucleotide therapy improves long-term survival in spinal muscular atrophy

An advanced peptide-oligonucleotide, Pip6a-morpholino phosphorodiamidate oligomer (PMO), which demonstrates potent efficacy in both the CNS and peripheral tissues in severe SMA mice following systemic administration following a systemic route with peptide delivery.

Functional correction in mouse models of muscular dystrophy using exon-skipping tricyclo-DNA oligomers

Although current naked AONs do not enter the heart or cross the blood-brain barrier to any substantial extent, it is shown that systemic delivery of tcDNA-AONs promotes a high degree of rescue of dystrophin expression in skeletal muscles, the heart and, to a lesser extent, the brain.
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