Amanda Almacellas, PhD, University College London, London, UK, shares an overview of her work investigating KCNA1 gene therapy as a novel treatment approach for focal cortical dysplasia (FCD) type II. FCDs are the most common causes of medically refractory epilepsy in children. FCD type II, a more severe form of cortical dysplasia, is the most common pathology found in pediatric epilepsy surgery. There is a substantial need for new treatments in this space, as resective surgery is not always effective and often precluded by the location of the malformation. Dr Almacellas has therefore been working on developing a gene therapy for FCD type II. The AAV-vector based approach delivers copies of a modified KCNA1 gene, which encodes potassium channel Kv1.1 and is downregulated by mTOR hyperactivation in FCD type II. The therapy was then tested in a mouse model shown to recapitulate the FCD pathology seen in humans, which resulted in a 64% reduction in seizure frequency over 4 weeks and no worsening of performance in tests of frontal lobe function. This interview took place at The BNA 2023 International Festival of Neuroscience in Brighton, UK.
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Transcript (edited for clarity)
Focal cortical dysplasias are malformations of the cortical development. I’m focusing on the type II, which is the one that elicits more frequently drug resistant epilepsy and in fact the most effective current treatment right now for it is resective surgery, which is why the major part of children who undergo brain surgery is because they are being treated for these seizures of focal cortical dysplasia too...
Focal cortical dysplasias are malformations of the cortical development. I’m focusing on the type II, which is the one that elicits more frequently drug resistant epilepsy and in fact the most effective current treatment right now for it is resective surgery, which is why the major part of children who undergo brain surgery is because they are being treated for these seizures of focal cortical dysplasia too. The bad thing is that these resective surgery is just effective in about 60% of cases and it’s not always a viable option because it depends on where the malformation of the cortex is located in the brain. That is why we are working to validate gene therapy, which would make a huge difference in this cohort of patients that don’t have an available treatment right now.
First of all, I need to introduce a bit the mouse model that that I have been using for that. It’s a mouse model that is based on mTOR hyperactivation in neuronal progenitors because it’s the major cause of focal cortical dysplasia type II in patients. And the gene therapy approach is a engineered potassium channel that has already been validated for temporal lobe epilepsy in the department. So I’m introducing the mouse model because apart from the engineered potassium channel being an already validated therapy for another kind of epilepsy, it’s important because the potassium voltage gated channel is downregulated because of mTOR hyperactivation and that has been seen in other types of disorders were mTOR hyperactivated in the neurons. So it was a double reason to use this approach in this for this gene therapy.
So what we did was to first of all characterize histologically and behaviorally the mouse model to validate it as reproducing the focal cortical dysplasia II main hallmarks and that involved the recording of the of the EEG with video confirmation of the spontaneous seizures that the animals had throughout 15 days of consecutive recording, for then injecting the gene therapy directly in the dysplastic focus which was encapsulated in an AAV9 viral vector. The virus was left there and the animals were left unbothered for 15 days so that the virus could incubate and reproduce this plastic focus and transduce cells, for then recording the animals for other 15 days to see how well the gene therapy was managing to decrease the seizure frequency. Apart from the seizure reduction, what we were also very interested on seeing is how this therapy addresses the comorbidities that the patients also have because they are they are also very burdensome in some cases. So the mice were tested for working memory as it is a function that that is normally impaired when you have a when you have a lesion in the in the prefrontal cortex, as is the case of these mice and social order recognition, which is a test that will that let you see if there’s autistic-like traits in your animals which is a very frequent characteristic of comorbidity in the focal cortical dysplasia II patients.
So they were tested for this for these cognitive tests before they were injected with a therapy. And in fact, the animals that showed spontaneous seizures due to the dysplastic focus, they showed an impairment in the both tests, as we expected. So after the gene therapy injection, we could see that the gene therapy achieves 64% reduction of the seizures in the animals that have been injected with EKC. And not only that, but also they were tested for the same tests after the recording and they showed no worsening on their cognition, which is a very good news as the same cannot be said in some kind of either resective surgery or some drug treatments. So it’s a very, very positive outcome and we are very excited about it.