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Gene therapy decreases seizures in a model of Incontinentia pigmenti
Author(s) -
Dogbevia Godwin K.,
Töllner Kathrin,
Körbelin Jakob,
Bröer Sonja,
Ridder Dirk A.,
Grasshoff Hanna,
Brandt Claudia,
Wenzel Jan,
Straub Beate K.,
Trepel Martin,
Löscher Wolfgang,
Schwaninger Markus
Publication year - 2017
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.24981
Subject(s) - incontinentia pigmenti , genetic enhancement , medicine , epilepsy , vector (molecular biology) , viral vector , adverse effect , gene , pharmacology , cancer research , bioinformatics , immunology , pathology , biology , genetics , recombinant dna , psychiatry
Objective Incontinentia pigmenti (IP) is a genetic disease leading to severe neurological symptoms, such as epileptic seizures, but no specific treatment is available. IP is caused by pathogenic variants that inactivate the Nemo gene. Replacing Nemo through gene therapy might provide therapeutic benefits. Methods In a mouse model of IP, we administered a single intravenous dose of the adeno‐associated virus (AAV) vector, AAV‐BR1‐CAG‐NEMO, delivering the Nemo gene to the brain endothelium. Spontaneous epileptic seizures and the integrity of the blood–brain barrier (BBB) were monitored. Results The endothelium‐targeted gene therapy improved the integrity of the BBB. In parallel, it reduced the incidence of seizures and delayed their occurrence. Neonate mice intravenously injected with the AAV‐BR1‐CAG‐NEMO vector developed no hepatocellular carcinoma or other major adverse effects 11 months after vector injection, demonstrating that the vector has a favorable safety profile. Interpretation The data show that the BBB is a target of antiepileptic treatment and, more specifically, provide evidence for the therapeutic benefit of a brain endothelial‐targeted gene therapy in IP. Ann Neurol 2017;82:93–104