Author: Dr Linda Popplewell, 25th July 2019
The British Society for Gene Therapy, as BSGCT was originally named, was founded seventeen years ago by a number of pioneers in the field including Prof George Dickson. On 3rd July this year, Prof Dickson enjoyed his official retirement party from his position of Chair of Molecular Cell Biology at Royal Holloway University of London. In recognition of his incredible contribution to the advancement of gene therapy, this blog is dedicated to him and his work.
Professor Dickson spent most of his career studying neuromuscular disease and muscle cell biology and developing gene therapies for muscular dystrophies. Milestones in his research history include the first cloning of an intact dystrophin gene, the discovery of the role of cell adhesion molecules in muscle stem cell fusion, the first identification of utrophin, and the first description of exon skipping in Duchenne muscular dystrophy (DMD). Professor Dickson has also conducted notable research into gene therapy for atherosclerosis, and genetic vaccination against HIV/AIDS.
Professor Dickson has worked tirelessly to promote gene therapy, acting as General Secretary and Board Member for the BSGT (2002-2010), President, Vice-president and General Secretary of ESGCT (2002-2008), and as committee member of the European Medicine Agency Committee for Advanced Therapeutics (Gene and Cell Therapies). With over 230 publications, his research group at Royal Holloway has pioneered the enabling technologies for the development of genetic therapies for incurable inherited diseases of muscle, such as DMD. His two notable contributions to the gene therapy field, amongst many others, are as follows:
Antisense materials and strategies for exon skipping technology underpinning clinical trials and formal medicines authorisation for treatment of DMD
In 1996, Prof Dickson’s team was the first to demonstrate that antisense oligonucleotides (AOs) could be used to induce therapeutic exon skipping in cellular and animal models of DMD. The outcome in animal studies was the effective cure of the DMD condition, and AOs have been optimised for certain mutations that cause the human disease. This has led to drug development and demonstrated proof-of-concept trials. Clinical trials continue, but one such new medicine was conditionally approved by the FDA for DMD on the 19th September 2016, and a second, is the subject of multicentre clinical trial. Demand for the approved AO has been the main contributing factor for the impressive $146.4 million increase in annual net revenue for Sarepta, the company that has licensed it. More importantly, this AO has had major impact on the lives and clinical outlook of patients and families. This AO could treat 13% of all DMD patients. Every week in the UK, two families receive the devastating diagnosis of DMD and it is estimated that there are currently 2,500 patients in the UK and 300,000 patients worldwide. This AO could therefore provide a life-changing therapy to 325 patients in the UK and 39,000 patients worldwide.
For the second AO, named golodirsen, a Phase 1/2 study (NCT02310906) continues to assess the safety, tolerability, efficacy, and pharmacokinetics of this AO. On the basis of exciting results from this trail, the FDA accepted a New Drug Application (NDA) seeking accelerated approval of this AO on February 14, 2019 and provided a regulatory action date of August 19, 2019 for this AO. This AO has been highlighted by Optum recently as the top drug to watch in 2019. This AO would provide a therapy for 8% of all patients i.e. 200 patients in the UK, and 24,000 patients worldwide. Collectively the patented AOs could provide benefit to over 37% of all DMD patients i.e. 925 UK patients and 111,000 patients worldwide. With development, single exon skipping to restore dystrophin protein expression could be applicable to nearly two-thirds of patients.
Gene therapy materials and strategies for treatment of DMD.
Prof Dickson’s team has also pioneered lab-based cloning of dystrophin genes for gene addition therapy for DMD. Optimised systems have been developed encoding both the full wild-type dystrophin protein and micro-dystrophins compatible with adeno-associated viral delivery vectors. These recombinant genes are functional and complement dystrophin deficiency, and have been distributed and used in labs across the world developing DMD gene therapies, including for the first human clinical trial of gene therapy in DMD patients conducted in 2002 which showed proof of concept. Studies have since shown that the optimised microdystrophin gene therapy vectors from the Dickson lab are highly functional and yield sustained improvements in the pathology of dystrophin-deficient muscles in small and large DMD animal models. Orphan drug status has been awarded. With Genethon Labs, GOSH and others, a translational clinical trial program for Prof Dickson’s microdystrophin gene therapy is starting in late 2019. This therapy would provide a therapy with applicability to all DMD mutations; the contribution of this therapy if approved to the Duchenne field would be immense.
During his illustrious career, Prof Dickson has received numerous awards including ‘Scientist of the year award for DMD research’ from Muscular Dystrophy Campaign in 2014 in recognition of his world class disease-changing gene therapies. The BSGT promotes scientific excellence, training and education in the field. It is platform through which scientists, healthcare workers and patients can discuss issues surrounding the development and implementation of therapies. These guidelines, first drawn up by Prof Dickson and the other founding members, has governed his work throughout his research careers. As such, he has made an unquantifiable contribution to the gene therapy field.
We thank you George for everything you have achieved, not least the creation of BSG(C)T, and fighting for the advancement and acceptance of gene therapy as a strategy for treating genetic disease. Along with those who have had the pleasure and privilege of calling you supervisor, collaborator and friend, you leave a clear legacy and it will be an honour to continue your work.