Antisense Oligonucleotide Therapy for Neuromuscular Disease
Lead Research Organisation:
University of Oxford
Department Name: Physiology Anatomy and Genetics
Abstract
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.
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.
Technical Summary
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.
Planned Impact
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.
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.
Organisations
Publications
Betts C
(2021)
Dystrophin involvement in peripheral circadian SRF signalling
in Life Science Alliance
Betts CA
(2019)
Cmah-dystrophin deficient mdx mice display an accelerated cardiac phenotype that is improved following peptide-PMO exon skipping treatment.
in Human molecular genetics
Chwalenia K
(2022)
Exon skipping induces uniform dystrophin rescue with dose-dependent restoration of serum miRNA biomarkers and muscle biophysical properties
in Molecular Therapy - Nucleic Acids
Ezzat K
(2019)
The viral protein corona directs viral pathogenesis and amyloid aggregation.
in Nature communications
Forouhan M
(2022)
AR cooperates with SMAD4 to maintain skeletal muscle homeostasis.
in Acta neuropathologica
Hanson B
(2022)
Non-uniform dystrophin re-expression after CRISPR-mediated exon excision in the dystrophin/utrophin double-knockout mouse model of DMD.
in Molecular therapy. Nucleic acids
Klein AF
(2019)
Peptide-conjugated oligonucleotides evoke long-lasting myotonic dystrophy correction in patient-derived cells and mice.
in The Journal of clinical investigation
Kordala AJ
(2023)
PRMT inhibitor promotes SMN2 exon 7 inclusion and synergizes with nusinersen to rescue SMA mice.
in EMBO molecular medicine
Lim W
(2021)
Gene therapy with AR isoform 2 rescues spinal and bulbar muscular atrophy phenotype by modulating AR transcriptional activity
in Science Advances
Moazami MP
(2022)
RNase-H-mediated silencing in the CNS proves predictably nontrivial.
in Med (New York, N.Y.)
Rinaldi C
(2022)
AR cooperates with SMAD4 to maintain skeletal muscle homeostasis
Van Westering TLE
(2020)
Uniform sarcolemmal dystrophin expression is required to prevent extracellular microRNA release and improve dystrophic pathology.
in Journal of cachexia, sarcopenia and muscle
Vilchinskaya N
(2023)
Investigating Eukaryotic Elongation Factor 2 Kinase/Eukaryotic Translation Elongation Factor 2 Pathway Regulation and Its Role in Protein Synthesis Impairment during Disuse-Induced Skeletal Muscle Atrophy
in The American Journal of Pathology
Title | Synthesis of cell-penetrating peptide morpholino |
Description | Cell penetrating peptides are conjugated to neutrally charged morpholino oligonucleotides to improve cellular and tissue uptake |
Type Of Material | Technology assay or reagent |
Year Produced | 2009 |
Provided To Others? | Yes |
Impact | Utilised for pre-clinical studies for neuromuscular diseases such as Duchenne muscular dystrophy, spinal muscular atrophy and myotonic dystrophy |
Description | Action Duchenne Charity |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | Formal presentation on research |
Year(s) Of Engagement Activity | 2015,2016,2017 |
Description | Plenary Lecture, MDA Scientific Conference, Washington DC |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | The 2017 MDA Scientific Conference brings together influential professionals in the academic, government, industrial and clinical arenas who work in various ways to help drive scientific and therapeutic advancements and discoveries. Nearly 450 leaders in the neuromuscular field gather for this prestigious conference to share critical updates on a wide range of scientific topics. |
Year(s) Of Engagement Activity | 2017 |
URL | https://www.mda.org/conferences/2017-scientific-conference |
Description | Presentation at Action Duchenne |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other audiences |
Results and Impact | Presentation at a conference arranged by Action Duchenne and a Q and A panel |
Year(s) Of Engagement Activity | 2018,2019,2020 |