Antisense Oligonucleotide Therapy for Neuromuscular Disease

Neuromuscular diseases comprise a diverse group of mainly inherited conditions that typically affect muscles (including the heart muscle) and the brain, resulting in progressive degeneration of these tissues and leading ultimately to very significant morbidity and mortality. These diseases are exemplified by the disorder Duchenne muscular dystrophy (DMD) which is a uniformly fatal inherited muscle disease affecting ~1 in 3500 newborn boys, that arises due to defects in the dystrophin gene which abolish production of the dystrophin protein, a crucial protein for normal muscle and heart function. As a result DMD patients develop a slowly progressive muscle degeneration and weakness that results in loss of ambulation around 12 years of age and leading eventually to premature death due to respiratory or heart muscle failure when boys are typically in their twenties. Twenty years ago, the 1993 Nobel Prize in Physiology or Medicine was awarded to Roberts and Sharp for their landmark discovery of so-called 'split genes' and RNA splicing - what we now recognise as the essential process within human cells necessary for the expression of virtually all human genes. This paradigm-shift in scientific understanding led to the idea that developing medicines to target RNA and modulate its processing might be able to treat the severe neuromuscular diseases including DMD, spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS) - all devastating degenerative disorders affecting adults and children and representing great unmet medical need. In recent years while a number of experimental therapies have been developed for treating DMD, the approach of targeting RNA using antisense oligonucleotides (AONs) - so-called exon skipping - is perhaps the most advanced and most promising of all. In the last decade, the world-leading work of the Wood Laboratory and others has confirmed the potential of these AON medicines to make a major impact human health, especially for DMD. However at present major scientific challenges remain to be overcome in order that we can exploit the full potential of this therapeutic method. These challenges include; the very poor delivery of these large AON drugs to the crucial tissues of muscle, heart and brain; the very low activity of these drugs in muscle and the negligible activity in heart and brain; and our limited understanding of the links between drug activity and the desired clinical outcome in terms of preventing or reversing the progression of disease. The field is now sufficiently mature to move to the next level of understanding aimed at elucidating answers to these fundamental scientific questions which will lead to the more effective and widespread exploitation of targeting RNA to treat neuromuscular diseases. Our research will establish essential scientific knowledge on the determinants of effective RNA targeting in muscle, heart and brain, its limitations and potential to abrogate severe, life-threatening neuromuscular disease. It will also reveal fundamental knowledge on the brain, allowing us to understand the scientific basis on which targeting RNA within the brain and spinal cord might be seriously advanced to treat severe, adult neurological disease. This in turn will harness the full potential of targeting RNA for improvement of human health.