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Review
. 2018 Jan-Mar;21(1):3-8.
doi: 10.4103/aian.AIAN_298_17.

Recent Advances in Antisense Oligonucleotide Therapy in Genetic Neuromuscular Diseases

Ashok Verma  1
Affiliations
Review

Recent Advances in Antisense Oligonucleotide Therapy in Genetic Neuromuscular Diseases

Ashok Verma. Ann Indian Acad Neurol. 2018 Jan-Mar.

Abstract

Genetic neuromuscular diseases are caused by defective expression of nuclear or mitochondrial genes. Mutant genes may reduce expression of wild-type proteins, and strategies to activate expression of the wild-type proteins might provide therapeutic benefits. Also, a toxic mutant protein may cause cell death, and strategies that reduce mutant gene expression may provide therapeutic benefit. Synthetic antisense oligonucleotide (ASO) can recognize cellular RNA and control gene expression. In recent years, advances in ASO chemistry, creation of designer ASO molecules to enhance their safety and target delivery, and scientific controlled clinical trials to ascertain their therapeutic safety and efficacy have led to an era of plausible application of ASO technology to treat currently incurable neuromuscular diseases. Over the past 1 year, for the first time, the United States Food and Drug Administration has approved two ASO therapies in genetic neuromuscular diseases. This overview summarizes the recent advances in ASO technology, evolution and use of synthetic ASOs as a therapeutic platform, and the mechanism of ASO action by exon-skipping in Duchenne muscular dystrophy and exon-inclusion in spinal muscular atrophy, with comments on their advantages and limitations.

Keywords: Dystrophy; eteplirsen; nusinersen; oligonucleotide; spinal muscular atrophy.

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Conflict of interest statement

There are no conflicts of interest.

Figures

Figure 1
Figure 1
Natural nucleotide and some chemical backbone modifications in synthetic nucleotides. NNt, natural nucleotide; PS, Phosphorothioate; NP, N3'-P5' Phosphoroamidate; OMe, 2'-O-methyl; MOE, 2'-O-methoxy-ethyl; LNA, locked nucleic acid; PMO, phosphoroamidate morpholino
Figure 2
Figure 2
Exon-skipping eteplirsen ASO recognizes DMD exon 51 in pre-mRNA and converts out-of-frame into in-frame smaller transcript of dystrophin. DMD, Duchenne muscular dystrophy; mRNA, messenger RNA; ASO, antisense oligonucleotide
Figure 3
Figure 3
Exon including nusinersen ASO recognizes SMN2 exon 7 in pre-mRNA and splices-in exon 7 to produce full length mRNA transcript and SMN protein. SMN, survival motor neuron; mRNA, messenger RNA; C>T, Cytosine to thymine base mutation; ASO, antisense oligonucleotide
See this image and copyright information in PMC

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