On-demand cell-autonomous gene therapy as a novel treatment for dogs with pharmacoresistant epilepsy

Epilepsy, the most common neurological disorder in pet dogs, has profound detrimental effects on both quality of life and lifespan. Treatment consists of long-term administration of antiseizure medications but around one third of affected dogs fail to respond and severe side effects of the medications are commonly encountered. As a result, many pet dogs are euthanised when their epilepsy becomes unmanageable. Novel treatment approaches are urgently needed in veterinary practice, as they are in human medicine, where epilepsy has a very similar prevalence. We have developed an entirely novel approach for treating seizures that utilises a viral vector to carry a gene therapy into the brain. The therapy specifically targets the overactive cells responsible for the initiation and propagation of seizures. It then reduces the activity of these overactive neurons but only for as long as they exhibit abnormal activity, so resulting in a persistent antiseizure effect without interfering with the function of normal surrounding neurons. If the seizures stop, the genetic therapy switches itself off, unless and until excessive activity recurs. We have previously demonstrated safety and efficacy of this antiseizure gene therapy in mice, with further efficacy data from human cells grown in culture. Furthermore, we have shown that the therapy does not interfere with physiological behaviours in mice. In this project we will work to optimise the gene therapy for use in dogs by testing different versions of the construct in dog cells grown in culture. We will then undertake a clinical trial in dogs with severe epilepsy, where the seizures are non-responsive to medication and in whom the quality of life is significantly compromised. Under general anaesthesia, the dogs will receive a single injection of the optimised construct and will then be monitored for at least 6 months. During this time, we will assess their seizure frequency and duration, their general brain health and behaviour, and we will monitor for any adverse effects of the treatment. The gene therapy will be injected into the cerebrospinal fluid (the fluid that bathes the brain) as this is a well-tolerated and non-invasive means of achieving widespread and focused access to the brain. A significant advantage of our therapeutic strategy is that it does not require identification of the location of the seizure-initiating neurons (which is generally not possible in dogs). The gene therapy will only be switched on in neurons that exhibit pathological activity. Thus, the epileptic foci are identified by the therapy and not a priori. In summary, we aim to test a first-of-its kind gene therapy for canine epilepsy with potential for long term seizure control following a single injection. This could be transformative to the lives of affected dogs, as well as their owners, and offers significant translation potential for other veterinary species and for people with a range of seizure disorders.