About Duchenne Treatments In The Pipeline Gene Therapies (inc. CRISPR) Dystrophin is the protein that is missing from the muscles cells of people with Duchenne. Mutations, or faults, in the DMD gene in people with Duchenne mean that their muscle cells do not make enough functional dystrophin. The DMD gene is one of the largest genes in the human body. Gene therapy approaches offer the possibility of delivering a functional copy of the dystrophin gene to muscle cells where it could restore production of the dystrophin protein. The most promising approach is based on the use of a harmless virus called Adeno-associated virus (AAV) which has been shown to effectively deliver genes to a range of different types of cells and tissues including muscle. One of the challenges is that the dystrophin gene is too big for the AAV vector. Researchers have made micro-dystrophin genes that have successfully been tested in animal models of Duchenne muscular dystrophy. A shortened but functional dystrophin is produced using this method. A phase I clinical trial has also been carried out in the US to test the safety of this approach in a very small number of boys. Solid Biosciences is working on a micro-dystrophin therapy and it is hoped that a clinical trial will be initiated in the coming months. Another potential approach that is still in early research is to deliver the whole gene using use two or three viruses, each carrying a different part of the DMD gene. The gene could then be assembled to form the blueprint for producing dystrophin in muscle cells. It is thought that this may offer an advantage over the delivery of micro-dystrophins as in theory full-length dystrophin may be produced. Gene editing (CRISPR/Cas9) CRISPR /Cas 9 is an exciting genetic engineering technique. It has two key components: Cas9 which is an enzyme that can cut DNA at a precise point CRISPR, a short strand of RNA, a chemical messenger Three research groups, working independently of one another, recently reported in the journal Science that they had used the Crispr-Cas9 technique to treat mice with a defective dystrophin gene. Each group loaded the DNA-cutting system onto a virus that infected the mice’s muscle cells, and ‘cut out’ an exon from the gene. Without the defective exon, the muscle cells made a shortened but functional dystrophin protein, giving all of the mice more strength. There are high hopes for the application of the CRISPR Cas9 technology for Duchenne however, for now, the state of the science and the corporate interest is classified as early stage. We at Duchenne UK have funded the work of Dr Ronald Cohn, Chief of Clinical and Metabolic Genetics and Co-director of the Centre for Genetic Medicine at SickKids in Canada, who has used CRISPR to remove a duplicated gene and restore protein function in cells from a child with Duchenne muscular dystrophy. We are also co-funding a £180,000 three-year gene editing project by Professor Francesco Muntoni, of University College London. His work, like Ronald Cohn’s, aims to remove an extra copy of the dystrophin gene, which causes Duchenne in around 15% of cases.