Gene therapy for refractory epilepsy

Epilepsy is the commonest serious neurological disorder, affecting approximately 1% of the population. People with active epilepsy have seriously disrupted lives. They cannot drive, experience social exclusion, have a high rate of depression and suicide, and are at risk of injury and even death during a seizure. About one quarter of people with epilepsy have seizures which are not prevented by any available medicines. In many cases, epilepsy is so disruptive that affected individuals are willing to undergo surgery to remove parts of their brains that generate seizures. Even this option is only open to relatively few people where the seizure-generating region is far from brain centres that control movement, language, vision and other essential functions. Most people with drug-resistant epilepsy have no realistic treatment options.

The main limitation to developing new medicines to treat epilepsy is that drugs taken as tablets affect nerve cells (neurons) throughout the brain, not just in the region responsible for triggering seizures. This results in side effects such as slowed thought processes, dizziness and altered mood, which prevent higher, potentially more effective, doses from being used. Moreover, most drugs used in epilepsy target similar mechanisms. There is an urgent need for new treatments that work in completely different ways.

We believe that we have found such a treatment that could be effective in a substantial proportion of people in whom seizures arise from an identifiable brain region. Instead of using drugs, we are adding a gene to a small number of neurons that are involved in seizure generation to make them less excitable, so preventing seizures from occurring.

Why should we undertake this work? We are a group of basic scientists and clinicians with in-depth knowledge of how neurons change as epilepsy develops, and how genes interact to make neurons more or less active. We have worked together for several years to develop a gene therapy that works in epilepsy. We identified an experimental model of epilepsy that is particularly difficult to treat, which resembles that seen in many people who are currently without effective treatment. We also worked with a collaborator in the USA to develop new ways of monitoring seizures automatically. Our results are very encouraging: not only does our treatment stop epilepsy from developing, but it also progressively stops seizures when epilepsy is already established. In essence, our treatment can 'cure' epilepsy, which has never been demonstrated previously. This is in spite of the fact that our treatment only targets a relatively small number of neurons. Gene therapy did not completely stop neurons from firing, and had no detectable side effects, and yet it completely prevented seizures.

Although our work received considerable media interest, we are not yet ready to start clinical trials. We have only tried one experimental model of epilepsy, and only using two different genes. To maximise the prospects for success in clinical trials, we need to improve our understanding of how our treatment works, ensure that we are using the best gene therapy tools, and test them in different situations. We will compare several different ways of calming neurons, and different ways of delivering the gene therapy. We will also test ways of switching on and off the calming effect on the neurons by using gene therapy that makes a small number of neurons sensitive to a drug that is normally inactive in the brain, or that allows brief pulses of light shone into the brain to stop selected neurons firing. We will put our gene therapy through a series of increasingly stringent tests, and look closely for any possible side effects.

By the end of our programme, complemented by safety studies, we aim to be ready to start clinical trials, raising hope for tens of thousands of people in the UK, and millions around the world, who currently suffer from uncontrolled seizures.

Our proposal builds upon our recent breakthroughs in preventing epileptogenesis and treating established epilepsy with gene therapy using lentiviral overexpression of the potassium channel Kv1.1 and the optogenetic inhibitor halorhodopsin. We will determine which gene therapy tools are most effective for suppressing seizures and which are best tolerated. This involves testing a carefully selected series of different channels (Kv1.1, Kir2.1, Kv7.2/3; synthetic receptors, and improved opsins), promoters (inducible and cell specific), and vectors for delivery (non-integrating, and AAV). We will investigate how well the evolution of focal seizures in our models maps onto human disease and how they are disrupted by gene therapy. We will also push to expand the therapeutic potential by testing our best candidates in additional models of focal epilepsy (visual cortex induced by tetanus toxin, ferric chloride and cobalt), limbic epilepsy, and generalised epilepsy. Much of our work is aimed at identifying the optimal strategy that can lead to clinical trials in patients with refractory epilepsy, but we will seek separate funding to perform toxicology studies and meet the regulatory requirements in preparation for such trials.

This is a revision of a highly ranked proposal entitled 'Viral manipulation of brain excitability for treatment of epilepsy' (September 2012), which received very positive evaluations but was criticised by two reviewers for focusing mainly on focal neocortical epilepsy with less attention to temporal lobe epilepsy. Focal neocortical epilepsy actually represents a greater unmet need than TLE, which can in many cases be treated by surgery. We recently audited our epilepsy practice and confirmed that 56% of patients referred for consideration of surgery had neocortical epilepsy. We have included pilot data acquired since the first submission and made further alterations and clarifications to address other points in the Case for Support.

The potential to have an impact: Approximately 1% of the population is affected by epilepsy, of whom over 20% continue to have seizures despite optimal pharmacotherapy. Further refinements in small molecule antiepileptic drugs are unlikely to alter this statistic. Surgery is only feasible in a small proportion of patients. Approximately 150,000 people in the UK have no realistic treatment options, and continue to have seizures, and experience major co-morbidities and social exclusion. The annual risk of sudden unexpected death in refractory epilepsy is around 2%, with a cumulative life-time risk between 7 and 40%. The annual cost of epilepsy to the European Union was estimated at Euro 15.5 billion (2004). The treatment gap is immense, and epilepsy research is underfunded in comparison to diseases of comparable impact. Per patient, Parkinson's disease and multiple sclerosis research receive 7 times more funding from the NIH (Meador, Neurology 2011).

Potential clinical impact: Of the advanced treatments that have been contemplated in refractory epilepsy gene therapy is the most likely to reach clinical trials, because the vectors have been refined and tested in other disorders. Our work to date has identified a highly effective and well tolerated treatment that could be translated to clinical trials. However, the aim of this proposal is to explore different refinements to the gene therapy tool, and test their applicability to different forms of focal epilepsy. This will form the scientific basis for clinical trials, which we anticipate can begin in 5-10 years.

Potential patient impact: A successful outcome of clinical trials could have a major impact on the quality of life of people with refractory epilepsy. Indeed, gene therapy, if successful could even be offered to people who are currently candidates for surgical resection. If the gene therapy is unsuccessful they could still proceed to resection (which would remove the transduced region and allow it to be studied with electrophysiological and other methods). If, on the other hand, the gene therapy is successful it would spare patients from a major irreversible surgical procedure with considerable risks to cognitive, sensory or motor function.

Neuroscience research: A safe and effective method of regulating the excitability of targeted neurons is a tool that will be important for neuroscience research as well as being applicable to other neurological and psychiatric conditions. The EEG monitoring system has already been applied in other research areas and the EEG analysis methods are being used in human EEG.

The wider public: there is a strong interest in treating the most resistant forms of epilepsy, and as this disease is common, a large proportion of the public will know someone with epilepsy. An entirely new route to treatment will have an impact on many families.

Timescales: During the course of the project we will present data at charities and symposia that will reach our academic and clinical beneficiaries. Our major publications will fall towards the end of the project, by which time we anticipate that our findings will be informing other studies of gene therapy tools in epilepsy. We are actively investigating strategies for increasing clinical translation, and we are already investigating pre-clinical studies to move our gene therapy tools into phase I/II trials.

Skills for staff on project: The staff will gain advanced skills in in vivo and in vitro electrophysiology (including patch clamp), viral manipulation, and models of epilepsy. Skilled electrophysiologists are in high demand; thus we anticipate that researchers hired on this project will be competitive for future positions.

In summary, the beneficiaries of the research are people with epilepsy, society as a whole because of the size of the economic impact of the disease, and other researchers who can tap into the technical developments that we are supporting.