{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T17:00:55Z","timestamp":1790701255624,"version":"4.1.0"},"reference-count":41,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2023,12,15]],"date-time":"2023-12-15T00:00:00Z","timestamp":1702598400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["V034758\/1"],"award-info":[{"award-number":["V034758\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/S011005\/1"],"award-info":[{"award-number":["MR\/S011005\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000295","name":"Epilepsy Research UK","doi-asserted-by":"publisher","award":["F1701"],"award-info":[{"award-number":["F1701"]}],"id":[{"id":"10.13039\/501100000295","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000295","name":"Epilepsy Research UK","doi-asserted-by":"publisher","award":["F1901"],"award-info":[{"award-number":["F1901"]}],"id":[{"id":"10.13039\/501100000295","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["212285\/Z\/18\/Z"],"award-info":[{"award-number":["212285\/Z\/18\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,2,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Focal cortical dysplasias are a common subtype of malformation of cortical development, which frequently presents with a spectrum of cognitive and behavioural abnormalities as well as pharmacoresistant epilepsy. Focal cortical dysplasia type II is typically caused by somatic mutations resulting in mammalian target of rapamycin (mTOR) hyperactivity, and is the commonest pathology found in children undergoing epilepsy surgery. However, surgical resection does not always result in seizure freedom, and is often precluded by proximity to eloquent brain regions. Gene therapy is a promising potential alternative treatment and may be appropriate in cases that represent an unacceptable surgical risk. Here, we evaluated a gene therapy based on overexpression of the Kv1.1 potassium channel in a mouse model of frontal lobe focal cortical dysplasia. An engineered potassium channel (EKC) transgene was placed under control of a human promoter that biases expression towards principal neurons (CAMK2A) and packaged in an adeno-associated viral vector (AAV9). We used an established focal cortical dysplasia model generated by in utero electroporation of frontal lobe neural progenitors with a constitutively active human Ras homolog enriched in brain (RHEB) plasmid, an activator of mTOR complex 1. We characterized the model by quantifying electrocorticographic and behavioural abnormalities, both in mice developing spontaneous generalized seizures and in mice only exhibiting interictal discharges. Injection of AAV9-CAMK2A-EKC in the dysplastic region resulted in a robust decrease (\u223c64%) in the frequency of seizures. Despite the robust anti-epileptic effect of the treatment, there was neither an improvement nor a worsening of performance in behavioural tests sensitive to frontal lobe function. AAV9-CAMK2A-EKC had no effect on interictal discharges or behaviour in mice without generalized seizures. AAV9-CAMK2A-EKC gene therapy is a promising therapy with translational potential to treat the epileptic phenotype of mTOR-related malformations of cortical development. Cognitive and behavioural co-morbidities may, however, resist an intervention aimed at reducing circuit excitability.<\/jats:p>","DOI":"10.1093\/brain\/awad387","type":"journal-article","created":{"date-parts":[[2023,11,20]],"date-time":"2023-11-20T15:22:21Z","timestamp":1700493741000},"page":"542-553","source":"Crossref","is-referenced-by-count":42,"title":["Anti-seizure gene therapy for focal cortical dysplasia"],"prefix":"10.1093","volume":"147","author":[{"given":"Amanda","family":"Almacellas Barbanoj","sequence":"first","affiliation":[{"name":"Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, University College London , London WC1N 3BG , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert T","family":"Graham","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, University College London , London WC1N 3BG , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benito","family":"Maffei","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, University College London , London WC1N 3BG , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenna C","family":"Carpenter","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, University College London , London WC1N 3BG , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Leite","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, University College London , London WC1N 3BG , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin","family":"Hoke","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, University College London , London WC1N 3BG , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felisia","family":"Hardjo","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, University College London , London WC1N 3BG , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Scott-Solache","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, University College London , London WC1N 3BG , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christos","family":"Chimonides","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, University College London , London WC1N 3BG , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Schorge","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Physiology and Pharmacology, University College London , London WC1E 6BT , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6696-3545","authenticated-orcid":false,"given":"Dimitri M","family":"Kullmann","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, University College London , London WC1N 3BG , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"Magloire","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, University College London , London WC1N 3BG , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3963-9296","authenticated-orcid":false,"given":"Gabriele","family":"Lignani","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, University College London , London WC1N 3BG , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,12,15]]},"reference":[{"key":"2024031915215335600_awad387-B1","doi-asserted-by":"crossref","first-page":"1648","DOI":"10.1056\/NEJMoa1703784","article-title":"Histopathological findings in brain tissue obtained during epilepsy surgery","volume":"377","author":"Blumcke","year":"2017","journal-title":"N Engl J Med"},{"key":"2024031915215335600_awad387-B2","doi-asserted-by":"crossref","first-page":"1344","DOI":"10.3390\/ijms23031344","article-title":"Cortical dysplasia and the mTOR pathway: How the study of human brain 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focal cortical dysplasia type IIA","volume":"84","author":"Hu","year":"2018","journal-title":"Ann Neurol"},{"key":"2024031915215335600_awad387-B6","doi-asserted-by":"crossref","first-page":"105026","DOI":"10.1016\/j.nbd.2020.105026","article-title":"PI3K isoform-selective inhibition in neuron-specific PTEN-deficient mice rescues molecular defects and reduces epilepsy-associated phenotypes","volume":"144","author":"White","year":"2020","journal-title":"Neurobiol Dis"},{"key":"2024031915215335600_awad387-B7","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1016\/j.ajhg.2017.01.030","article-title":"Somatic mutations in TSC1 and TSC2 cause focal cortical dysplasia","volume":"100","author":"Lim","year":"2017","journal-title":"Am J Hum Genet"},{"key":"2024031915215335600_awad387-B8","doi-asserted-by":"crossref","first-page":"1445","DOI":"10.1038\/nm.3982","article-title":"An AKT3-FOXG1-reelin network underlies defective migration in human focal malformations of cortical development","volume":"21","author":"Baek","year":"2015","journal-title":"Nat Med"},{"key":"2024031915215335600_awad387-B9","doi-asserted-by":"crossref","first-page":"11753","DOI":"10.1038\/ncomms11753","article-title":"Convulsive seizures from experimental focal cortical dysplasia occur independently of cell misplacement","volume":"7","author":"Hsieh","year":"2016","journal-title":"Nat Commun"},{"key":"2024031915215335600_awad387-B10","doi-asserted-by":"crossref","first-page":"e3001279","DOI":"10.1371\/journal.pbio.3001279","article-title":"RHEB\/mTOR hyperactivity causes cortical malformations and epileptic seizures through increased axonal connectivity","volume":"19","author":"Proietti Onori","year":"2021","journal-title":"PLos Biol"},{"key":"2024031915215335600_awad387-B11","doi-asserted-by":"crossref","first-page":"4207","DOI":"10.1172\/JCI127032","article-title":"Brain somatic mutations in MTOR reveal translational dysregulations underlying intractable focal 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