Each week in the UK, two families receive devastating Duchenne muscular dystrophy (DMD) diagnosis; there are currently around 2,500 patients in the UK and 300,000 patients worldwide with the disease.
Developing genetic therapies
Treatment options have been restricted to addressing the disease phenotype, rather than the genetic defect itself. Research at Royal Holloway by Professor George Dickson and Dr Linda Popplewell is focused on developing genetic therapies for the treatment of muscular dystrophies, in particular DMD. DMD, a fatal heritable condition caused by multiple defects in the gene encoding dystrophin, affecting new-born boys, is characterised by progressive muscle degeneration and weakness
The impact of our research programme is based on halting the progression of disease using antisense oligonucleotides (AOs) to induce exon skipping. Exon skipping re-opens the reading frame in the mutated DMD mRNA leading to expression of truncated yet functional dystrophin protein. Royal Holloway was the first to demonstrate that AOs could induce therapeutic exon skipping and restore dystrophin protein expression in a model of DMD. Since then, RHUL has optimised AOs and four patents have been granted and licensed to pharmaceutical companies.
Treatment options for DMD have been limited to controlling symptoms and providing palliative care. Current recommended management is daily corticosteroid administration to control the inflammation that arises within skeletal muscle as a result of the disease; long term corticosteroid treatments carries serious body-wide side effect risk.
Our research has been instrumental in advancing the treatment options for patients that are specifically targeted to address the genetic basis of DMD. In contrast to corticosteroid treatment, ExonDys-51 and VyonDys-53, two AOs collaboratively developed by RHUL, effectively restore dystrophin protein expression in skeletal muscle in treated patients. The dystrophin protein expressed is demonstrated to be functional; treatment with ExonDys-51 for more than 2 years has been reported to prevent further deterioration in muscle activity. For a severe progressive disease like DMD, this imparts paramount therapeutic benefit.
Life expectancy and quality of life
The restored dystrophin protein expression seen with ExonDys-51 treatment is reported to improve life expectancy. In patients whose treatment began before loss of lower limb function, ambulation is maintained. In older wheelchair-bound patients, ExonDys-51 acts to preserve upper limb and diaphragm functionality. This genetic medicine leads to an enhanced quality of life in all treated patients.
The research has resulted in two commercially available drugs, VyonDys-53 (patented by RHUL and approved by the US Federal Drugs Agency) and Exon-Dys-51 (collaboratively optimised by RHUL and others). Together these two drugs have the potential to provide therapeutic benefit to nearly 25% of patients.