Our Research Research we are funding Our Research Strategy Duchenne Muscular Dystrophy research has gathered pace over the past few years. There is a growing pipeline of new investigational compounds and drugs entering the late stage of the clinical trial process. Whilst this is incredibly encouraging, we need more progress so that the best possible treatments/therapeutic interventions can be made available as quickly as possible to everyone living with Duchenne Muscular Dystrophy. Background Action Duchenne, is a well-established parent-led Duchenne patient organisation in the UK with its primary aim of supporting research advances that will lead to Duchenne treatments. We actively monitor medical advances in the area and collaborate with the healthcare, scientific and wider patient community, to ensure we fund the most innovative and cutting-edge research. In May 2013, Action Duchenne published the first research strategy in Duchenne, which outlined our recommendations and funding priorities, moving forward. Our strategy was endorsed and recognised by all sectors of the Duchenne community. The focus of our research strategy Underpinning this research strategy is the rationale and understanding of the downstream effects of having a dysfunctional copy of the Duchenne gene, which is explained directly below. The dystrophin protein normally sits in the membrane that surrounds muscle fibres where it serves as a “coat hanger” around which other proteins associate (Figure 1). When you are missing dystrophin, you are missing an important stabiliser which helps protect the cell membrane from damage during muscle fibre contraction and it is a key molecule that helps form a link between the internal architecture of the cell and the matrix on the outside of the cell. When dystrophin is absent or non-functional, the so called Dystrophin Associated Protein Complex doesn’t function correctly at the membrane and a cascade of biochemical functions and signalling pathways are interrupted – with the results that we see in people living with Duchenne. Figure 1 – Dystrophin, showing its position at the cell membrane – the long purple molecule running from the “N terminus” to the “C-terminus”. Funding the best possible research Our key tenet as an organisation is to be a leader in funding the best possible research that may perhaps lead to a cure for all those living with Duchenne muscular dystrophy. We believe the closest possible solution to achieving this goal is to advance gene therapy (introduce a functional copy of the gene), which in theory could treat the whole Duchenne population (Figure 2). Also, without treating the underlying cause in the long-term, we cannot stop further variations and disruptions in dystrophin, the largest gene in the human body. Figure 2 Basic mechanisms of gene therapy Cocktail approach The executive summary of the research strategy also explained the complexity of the pathophysiology of Duchenne and that current expert opinion suggests a possible cocktail approach, targeting multiple pathways of the dystrophin-associated protein complex (Figure 3). Figure 3 Potential different targets for Duchenne therapy Exon skipping We also want to work closely with the scientific community on looking at improving the efficiency of current exon skipping technologies. Exon skipping is based on antisense chemistries which block the messenger mRNA from excluding an exon that sits next to the deleted mutation, thus restoring the reading frame (Figure 4). Two main chemistries based on this technology have progressed in late phase trials, with some encouraging findings, but have been halted by the regulatory authorities, pending further data. Whilst we await these decisions and moving forward, we can help support research that will further optimise the efficiency of this technique, potentially with combination treatment. Figure 4 Exon skipping technology using antisense oligonucleotides (AON) restores the genetic code. Courtesy of Dr Annemieke Aartsma-Rus, Leiden University. Biomarker development We also want to contribute towards the framework of biomarker development. There is a consensus to work on all three types of biomarkers, but advances particularly towards therapeutic monitoring, with the aim of potential adoption as secondary or tertiary endpoints for clinical trials. There are three types of biomarkers: – Diagnostic biomarkers (telling you something is wrong) – Prognostic biomarkers (predicting disease course and/or severity) – Therapeutic monitoring biomarkers (can predict whether a therapy will work or is working) Funding priorities Based on the above our current priorities for funding are as outlined below; To seek research proposals to advance gene replacement technology. Gene replacement technology or ‘gene therapy’ hopes to introduce a functional copy of the dystrophin gene and restore expression at the neuromuscular membrane. To investigate other treatment modalities and to choose one surrogate protein/target to investigate in combination (in a suitable animal model). To work alongside the scientific community to better understand current and emerging advances in exon skipping chemistries and strategies. Based on emerging expertise, support for an individual or collaborative effort in investigating novel or validated biomarkers for translational research and clinical trial endpoints. Information on individual strands of research within these four main priorities are included in our research strategy document.