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.

The use of antisense oligonucleotides (AONs) to target RNA to treat human neuromuscular disease represents a major paradigm shift in medical science. This is exemplified by progress towards a therapy for Duchenne muscular dystrophy (DMD), a catastrophic neuromuscular disorder arising due to out-of-frame mutations in the dystrophin gene and characterised by progressive muscle wasting and premature death. However, while AON-based therapy for DMD is perhaps the most promising of all current therapeutic approaches, this is a critical time for the field. Major scientific barriers to success exist, related to poor systemic delivery of current generation AONs, sub-optimal efficacy in muscle and negligible efficacy in heart and brain, and lack of detailed mechanistic understanding pertaining to AON cell-targeting, cell-uptake, intracellular trafficking and efficacy in relation to pathophysiological outcomes. In this MRC Programme we will build on the international leadership of the Wood Laboratory and on our strong track record over the last 5 years, during which we have successfully begun to address many of these challenges, developing advanced AON chemistries and providing mechanistic insight into AON function and into the requirements for successful targeting of muscle, heart and brain. We now aim to address the fundamental questions that will enable the full potential of AON targeting of RNA to be successfully exploited. Our central objectives include: understanding the chemical and biological requirements for AON efficacy in the neuromuscular system; establishing effective AON targeting of muscle, heart and brain and understanding causal links between pharamacodynamic efficacy and pathophysiological outcome; and elucidating the molecular mechanisms. Our work will open the door to effectively treating numerous neuromuscular diseases, where AON-based precision medical interventions have the potential to transform health outcomes in these areas of high unmet medical need.

Our research will have major impact on health outcomes, on industrial and commercial entities, on training the next generation of neuromuscular scientists, on policy makers, and on patients and patient-based organizations.


Antisense oligonucleotide (AON) targeting of RNA has shown promise as a novel therapy for DMD and two AON drugs being developed by BioMarin and Sarepta are likely to gain accelerated FDA approval in the next 12 months, however current AON efficacy is sub-optimal meaning that the likely clinical benefit will be limited. Our proposed Programme to develop next-generation AONs thus has the potential to transform the field, leading to effective treatments for numerous neuromuscular diseases, where AON-based precision medical interventions have the potential to transform health outcomes in areas of high unmet medical need. The potential impact for human health is therefore high.

The proposed Programme will also have a significant industrial / commercial impact. Numerous companies are currently developing novel therapies for DMD and related diseases (e.g. BioMarin, Sarepta Therapeutics, Pfizer, Shire, Isis Pharmaceuticals and Summit Plc). We will work closely with industry as the Programme develops to capitalise on the applications of the AON therapeutic approach for DMD, for other related neuromuscular diseases and ultimately also for other diseases where the knowledge and methods in relation to the systemic delivery of AONs might have utility. In doing so we will build on the relationships and links which have been established over the course of the last 5 years, working with small biotechnology companies e.g. Sarepta Therapeutics and larger industry partners e.g. Pfizer to advance our fundamental science and ensure that our knowledge, know-how and relevant intellectual property are exploited to achieve the desired impact. All intellectual property developed during the course of the Programme is managed by Isis Innovation, the technology transfer company of the University of Oxford, who will assess, protect and commercialise the IP generated from the project before engaging with potential industrial end-users.

A significant impact of the present Programme will be in the training and development of scientific researchers involved in the various inter-related projects. The staff working on the grant will be trained not only in the molecular, cellular, bioinformatic and neuromuscular techniques associated with the research programme but also in the rigour of reporting required for the development of new methods, new technologies and ultimately new medicines for treating human disease. Scientific staff will receive training in relation to conference presentations, interacting with industry and receive numerous opportunities to develop skills in public engagement. This will lead to highly effective communications skills and also to employment prospects not only in academia but also in the biotechnology and large pharma sectors.

Policy makers will also benefit directly from our work into development of new genetic therapies. They include those developing healthcare policy in the UK and more widely trying to understand the likely impact of genomic medicine, those concerned with health economics in relation to genetic medicines and those concerned with regulation and approval of such medicines.

Finally, perhaps the most important set of beneficiaries who will be impacted by the outcomes of our work are DMD and neuromuscular disease patients themselves, their families and the many associated advocacy groups that work tirelessly and campaign strongly for effective therapies to treat these diseases. All will be interested to understand the potential of advanced AON methods for treating these severe diseases and how and over what timescale these are likely to confer benefit.