Abstract
Antisense therapy is an approach to fighting diseases using short DNA-like molecules called antisense oligonucleotides. Recently, antisense therapy has emerged as an exciting and promising strategy for the treatment of various neurodegenerative and neuromuscular disorders. Previous and ongoing pre-clinical and clinical trials have provided encouraging early results. Spinal muscular atrophy (SMA), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS), Duchenne muscular dystrophy (DMD), Fukuyama congenital muscular dystrophy (FCMD), dysferlinopathy (including limb-girdle muscular dystrophy 2B; LGMD2B, Miyoshi myopathy; MM, and distal myopathy with anterior tibial onset; DMAT), and myotonic dystrophy (DM) are all reported to be promising targets for antisense therapy. This paper focuses on the current progress of antisense therapies in neurology.
Highlights
Antisense oligonucleotides (AOs) are short, synthetic nucleic acid sequences that selectively hybridize to target sequences in messenger RNA
Notwithstanding its slow progress, antisense remains a widely popular area of research in molecular biology, and with recent advancements in oligo chemistries and promising results from recent clinical trials it may well be that the day of AOs in the clinical arena in neurology is close at hand
Because the loss of HTT is associated with several deleterious consequences, the allele-specific silencing of mutant huntingtin protein (mHTT) is a promising therapeutic approach to treating Huntington’s disease (HD) [58,61,179,236], some studies have shown significant beneficial effects from the co-suppression of both mutant and wild-type alleles [237,238,239]
Summary
Antisense oligonucleotides (AOs) are short, synthetic nucleic acid sequences that selectively hybridize to target sequences in messenger RNA (mRNA). After initially observing antisense-mediated RNA regulation in nature, investigations using model systems to test the feasibility of using synthetic AOs to reduce levels of specific mRNA transcripts quickly followed. Experiments showed that AOs were effective in reducing target transcripts and protein synthesis [2]. Despite promising early results, the use of AOs in disease therapy has been stymied by technical challenges and progress has been slow. Notwithstanding its slow progress, antisense remains a widely popular area of research in molecular biology, and with recent advancements in oligo chemistries and promising results from recent clinical trials it may well be that the day of AOs in the clinical arena in neurology is close at hand
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