Neuromuscular disorders (NMDs) are a frequent cause of loss of ambulation, chronic disability, and early death worldwide. An estimated 300
000 people suffer from NMDs in Europe alone. Some of these disorders have a genetic cause, with mutations in different genes leading to a variety of phenotypes that differ in severity and/or affected muscles.1
As yet, treatment is largely palliative and delays, but does not prevent the progressive loss of muscle and/or function and increasing disability. In principle, gene therapy to replace the defective gene is an attractive approach.2
However, whole body treatment is challenging for NMDs because of the tissues involved: ~30 to 40% of the human body consists of muscle, and delivery to the central nervous system is impeded by the blood–brain barrier. Although adeno-associated virus (AAV) is one of the few viral vector systems that efficiently infects muscle, it has a small cloning capacity.3
Not only do cDNAs of most NMD genes exceed this capacity, but also many genes are regulated by long and complex promoters, involving multiple start sites and complex alternative splicing.
For some NMDs (eg, myotonic dystrophy (DM)), a dominant-negative effect underlies the disease. For these, replacing the defective gene is unlikely to be therapeutic at all. Thus, it is not surprising that for NMDs, research also focuses on ways to restore gene expression at the (pre-) mRNA level. This can be achieved through antisense oligonucleotides (AONs), small synthetic RNAs, DNAs or analogs, which hybridize specifically to their target sequences.2
Today, AONs are in clinical trials for several applications (). They are relatively small (~10
kDa) and have more favorable biodistribution properties than, for example, plasmids.4
They can be produced on a large scale under GMP conditions much easier than viral vectors. For three of the major NMDs (Duchenne muscular dystrophy (DMD), Spinal muscular atrophy (SMA) and Myotonic dystrophy), AONs have therapeutic potential and are currently in various stages of translational trajectories.5, 6, 7, 8
Interestingly, although the tool is the same for each disease (AONs), it is tailored in different ways for the different NMDs (see below). For DMD, AONs are already in Phase IIa clinical trials and are generally considered the most promising therapy for this disease.7, 9
For SMA and DM, studies are only preclinical so far, but major advances have been made in the recent past5, 6, 8, 10
and clinical trials are likely to take place in the near future.
Overview of antisense oligonucleotide applications
Here, we will review the different therapeutic approaches for DMD, SMA and DM, and discuss the development toward clinical application of these treatments.