Abstract
Neuromuscular disorders such as Duchenne Muscular Dystrophy and Spinal Muscular Atrophy are neurodegenerative genetic diseases characterized primarily by muscle weakness and wasting. Until recently there were no effective therapies for these conditions, but antisense oligonucleotides, a new class of synthetic single stranded molecules of nucleic acids, have demonstrated promising experimental results and are at different stages of regulatory approval. The antisense oligonucleotides can modulate the protein expression via targeting hnRNAs or mRNAs and inducing interference with splicing, mRNA degradation, or arrest of translation, finally, resulting in rescue or reduction of the target protein expression. Different classes of antisense oligonucleotides are being tested in several clinical trials, and limitations of their clinical efficacy and toxicity have been reported for some of these compounds, while more encouraging results have supported the development of others. New generation antisense oligonucleotides are also being tested in preclinical models together with specific delivery systems that could allow some of the limitations of current antisense oligonucleotides to be overcome, to improve the cell penetration, to achieve more robust target engagement, and hopefully also be associated with acceptable toxicity. This review article describes the chemical properties and molecular mechanisms of action of the antisense oligonucleotides and the therapeutic implications these compounds have in neuromuscular diseases. Current strategies and carrier systems available for the oligonucleotides delivery will be also described to provide an overview on the past, present and future of these appealing molecules.
Highlights
The availability of novel drugs in genetics medicine can offer new opportunities for treating conditions for which there is currently no therapeutic strategy
antisense oligonucleotides (ASOs) can target specific regions as 50 /30 splice junctions or exonic/intronic splicing enhancer/silencer sites (ESEs or ISEs, exonic splicing silencers (ESSs) or intronic splicing silencers (ISS)) leading to the skipping/inclusion of an exon. This strategy can be used to: (i) restore the mRNA reading frame by exon skipping in diseases such as Duchenne Muscular Dystrophy (DMD) in which frame-shift deletions or non-sense mutations cause the functional protein loss; (ii) promote the inclusion of exons, as occurs in Spinal Muscular Atrophy (SMA) where ASOs induce the inclusion of the exon 7 in the SMN2 gene; (iii) introduce an out-of-frame deletion for reducing protein expression, as in Alzheimer disease or in Amyotrophic Lateral Sclerosis (Figure 2) [67]
Promising results have been obtained from pre-clinical studies and we report two additional examples of applying ASO strategies in the neuromuscular field
Summary
The availability of novel drugs in genetics medicine can offer new opportunities for treating conditions for which there is currently no therapeutic strategy. Proteins are the most common target of already approved drugs [1], research has intensively focused on the discovery of new biologically active molecules, which target the nucleic acids, as RNA or DNA [2]. Among these new compounds, antisense oligonucleotides (ASOs) have been recognized for the treatment of neurodegenerative disorders [3]. MRNAs, allows interference with the splicing mechanism, or regulation of protein translation, or RNA/protein binding In this way the ASO molecules can alter the expression of specific genes with a therapeutic application for pathologies that are not treatable with other known drugs [4,5]. This review will provide an update on the different antisense chemistries developed and the delivery systems currently available, and will describe their clinical applications in the neuromuscular fields
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