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

Lead Research Organisation: University College London
Department Name: Maternal & Fetal Medicine


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.

Technical Summary

Needs: Infant-onset epilepsy is debilitating and, when caused by mutations in the voltage- gated sodium channel NaV1.1 (Dravet syndrome), incurable and sometimes fatal. It is associated with widespread brain disease manifesting as cognitive and motor disorders which may be seizure-independent. Patients rarely live independently. Anti-epileptic drugs are ineffective. NaV1.1 is notoriously difficult to work with on a molecular basis; its incompatibility with bacterial amplification has stifled attempts at gene therapy, which requires large amount of DNA for vector synthesis
Rationale: Over the last 15 years, several gene therapy clinical trials have yielded remarkable results, including trials at UCL for inherited immunological and eye diseases and Haemophilia B. Dr Waddington performed preclinical studies in haemophiliac mice for the latter trial. Recently his team have cured several mouse models of devastating brain diseases including neuronopathic Gaucher Disease (Rahim et al. Hum Gene Ther 25(A14) 2014). The biotech company Touchlight Genetics has developed a process for enzymatic (non-bacterial) amplification of DNA. With Drs Waddington and Karda, they have used this DNA to produce high-titre lentivirus vectors. We aim to restore Nav1.1 expression in the nervous system of the Dravet mouse model by injecting a novel lentiviral vector. This aims to normalise electrophysiological properties, prevent seizures and brain damage Development plan: We propose to establish the first nervous-system-directed study for gene therapy of inherited epilepsy. Crucially, this will exploit enzymatic DNA amplification for high-purity vector production. Here, we request funding for preclinical studies to test vector synthesis feasibility, in vitro efficacy, in vivo potency and biodistribution. Gathered data will, in future, feed into the Investigational Medicinal Product Dossier to obtain Clinical Trial Authorisation from the Medicines and Healthcare Products Regulatory Agency

Planned Impact

Who will benefit from this research?
In addition to the specific academic beneficiaries that have been listed in the academic beneficiaries section above, the pharmaceutical industry, patients with other inherited epilepsies, the general public and the wider academic and clinical community will benefit from development of novel gene therapy strategies using Dravet syndrome as a paradigm. Benefits will occur as follows :
1. Benefits for Industry: The research outlined in this proposal is likely to be important to the pharmaceutical industry in two specific ways:
(i) There is currently renewed interest by the pharmaceutical industry, in development of gene therapy vectors, because conventional medicine is either poor or non-existent for a large cadre of inherited neurological diseases. The PI and Co-Is have had numerous meetings with scientists from other companies who are also keen to know the results from our investigation. As new findings emerge about the properties of the novel vector they will be shared with scientists at different companies and more widely as other interest develops.

(ii) Using our novel technology for vector synthesis and delivery may serve as a pathfinder for related channelopathies and inherited epilepsies, as well as other inherited neurological diseases of childhood. We have already engaged UCL Business in protecting potential intellectual property arising from this research.

2. Benefits for the General Public: The general public will benefit from this research, because it will help our understanding of the use of novel potentially curative approach to treatment of inherited epilepsy. The findings of biodistribution and toxicology experiments will have an educational impact. We will engage the UCL Public Engagement Unit as well as our Institute website to provide educational information about brain directed gene therapy as a way to get our new findings across to the general public including families of children affected by this, and related diseases.

3. Benefits for the wider academic and clinical community: In the long term health care professionals, both academic and clinical as well as patients will benefit from the work undertaken in this study especially if new knowledge about gene delivery to the young brain can lead to better drugs that can treat patients with inherited epilepsy and other neurological diseases. In the long term there may be impact on the well-being and quality of life of patients as well as economic benefits by saving health care costs also initiating activities in the UK-based pharmaceutical industry.


10 25 50
publication icon
Ahmed SG (2018) High-efficiency transduction of spinal cord motor neurons by intrauterine delivery of integration-deficient lentiviral vectors. in Journal of controlled release : official journal of the Controlled Release Society

publication icon
Baruteau J (2017) Expanding the phenotype in argininosuccinic aciduria: need for new therapies. in Journal of inherited metabolic disease

publication icon
Baruteau J (2019) Fetal gene therapy for neurodegenerative lysosomal storage diseases. in Journal of inherited metabolic disease

publication icon
Chan JKY (2019) Therapeutic expression of human clotting factors IX and X following adeno-associated viral vector-mediated intrauterine gene transfer in early-gestation fetal macaques. in FASEB journal : official publication of the Federation of American Societies for Experimental Biology

Description Appointed to board of Trustees for Epilepsy Research UK
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
Description UCL Celebrates the 3Rs
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Influenced training of practitioners or researchers
Description The invention provides expression vectors, nucleic acids, vector particles and methods of treatment involving these vector particles, comprising an engineered KCNA 1 gene encoding an edited Kv1.1 potassium channel, as well as methods of confirming the presence of engineered KCNA 1 mRNA in a cell. The features of the engineered KCNA 1 gene combine to advantageously enhance the translation and activity of the Kv1.1 protein and improve detection of KCNA 1 gene expression in a cell and can be used for example in the treatment of epilepsy and similar neurological disorders. 
IP Reference WO2018229254 
Protection Patent application published
Year Protection Granted 2018
Licensed No
Impact This patent is helping support our award to translate our gene therapy to a first in human clinical trial
Description Royal Society Summer festival presentation 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact This was a summer science 'lates' which meant running a both with a hands on activity for people attending the Royal Society Summer Science Festival. We presented an origami hands-on demonstration of how gene therapy uses viral shells to carry instructions for making healthy genes. The event was very well attended with over 3000 at the Royal society, and my personal booth (going by how many sheets of origami paper we gave out) had over 100 visitors, mostly from the general public but also some schools and university students.
Year(s) Of Engagement Activity 2018
URL https://royalsociety.org/science-events-and-lectures/2018/07/summer-science-lates/
Description Talk at the British Society for Gene and Cell Therapy Public Engagement Day, March 2019, Natural History Museum, Oxford 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact The British Society of Gene & Cell Therapy runs annual public engagement days where schools and public are invited to hear talks by researchers in the area of gene and cell therapy. There are also lunchtime activities around genetics, gene and cell therapy. After each talk, school children are often forthcoming with questions.
Year(s) Of Engagement Activity 2019
URL https://www.bsgct.org/public-engagement-day-2019/