MICA: Development of gene therapy for the incurable inherited childhood epilepsy, Dravet Syndrome

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Dravet syndrome is a rare, devastating infantile epilepsy. Before the age of two children suffer seizures, movement problems, cognitive impairment and may die. Often children can't talk, and suffer behavioural difficulties which imposes a tremendous burden on the family and carers. Children with Dravet have mutations in the SCN1A gene, which makes a protein "Nav1.1". This protein is vital for the functioning of neurons in the brain, and the mutations in this protein disrupt the normal balance of electrical activity in the brain. Unfortunately, this disease remains is incurable and drugs to treat Dravet do not work very well. They often have side effects, fail to fully control seizures, and don't improve other aspects of the disease such as the movement and cognitive problems. Administering drugs can also be a challenge, as Dravet children may struggle to swallow or reject food. There is a strain of mice which has a very disease to Dravet syndrome. It carries a similar mutation to that in Dravet children. This similarity to the human disease means that the mouse models of Dravet syndrome are very using for testing new treatments of Dravet. Gene therapy offers many benefits over drug therapy and surgery. Gene therapy is a treatment which, instead of simply treating the symptoms, addresses the cause of the disease by delivering the corrected copies of the SCN1A directly to the cells in the brain. Gene therapy use particles called "vectors" which resemble viruses, to deliver the DNA. Gene therapy has already been used to cure children with severe genetic diseases and promising results are now being seen with neurological diseases such as inherited Parkinsonism.However, gene therapy for Dravet syndrome faces several challenges. The SCN1A gene is large, and this limits incorporation into the most common gene therapy vectors. We have identified a vector which is capable of carrying the full length gene. This vectors has already been used in gene therapy clinical trials to treat adult patients with Parkinson's Disease. Another challenge that is particular to Dravet and SCN1A, is the extreme difficulty in making large amounts of gene in the laboratory, ready for delivery. This has thwarted gene therapy laboratories around the world. We have partnered with a company called Touchlight Genetics who can make large amounts DNA, using purified enzymes. Therefore, we hope to be able to make large amounts of SCN1A which will allow us to make gene therapy vector to treat and potentially reverse the cause of Dravet. Firstly, Touchlight Genetics will make large amounts of DNA with which we can make a lentivirus vector containing the human SCN1A gene. From this we will make gene therapy vectors and test that they work in brain cells in a dish ("in vitro"). These cells will be neurons from the mice which have mutant non-functional SCN1A genes. We will measure the electrical currents (a technique called patch clamping) to detect whether our gene therapy has successfully delivered working copies of the SCN1A gene, so that the cells can make working Nav1.1 protein. If this works, we will test the gene therapy in in mutant mice. We will inject the gene therapy vector into their brain on the day of birth and look for symptoms of the diseases. We will compare them to normal, unaffected mice. We will study their brains for any evidence of disease and may measure electrical currents to see how much of the Nav1.1 protein was made after gene therapy. We will also check that the gene therapy is safe, by injecting vector into brains of some normal mice (carrying no SCN1A mutation). This project is aimed at developing a medicine to treat a devastating disease for which there is presently no cure. If this project works, the technologies we have used in making and delivering this gene therapy may benefit many other childhood diseases where gene therapy has previously proven to be difficult.