Systemic delivery of antagomirs during blood-brain barrier disruption is disease-modifying in experimental epilepsy

• DOI: 10.1016/j.ymthe.2021.02.021
• Publication Date: 2021-02-21T11:51:48Z
• Authors: Cristina R. Reschke; Luiz F.A. Silva; Vamshidhar R. Van...; Massimo Rosso; Bastian David; Brenton L. Cavanagh; Niamh M.C. Connolly; Gary P. Brennan; Amaya Sanz-Rodriguez; Catherine Mooney; Aasia Batool; Chris Greene; Marian Brennan; Ronan M. Conroy; Theodor Rüber; Jochen H.M. Prehn; Matthew Campbell; R. Jeroen Pasterkamp; David C. Henshall
• Keywords: 0301 basic medicine; 610; Noncoding RNA; noncoding RNA; Mice; 03 medical and health sciences; antiepileptic drug; Drug Discovery; Genetics; Animals; Genetic Predisposition to Disease; Gene Silencing; chemoconvulsant; Status epilepticus; Molecular Biology; Pharmacology; Antisense oligonucleotides; status epilepticus; Epilepsy; antagomirs; Gene Transfer Techniques; Antagomirs; Disease Management; Genetic Therapy; Epileptogenesis; Chemoconvulsant; 3. Good health; Disease Models, Animal; MicroRNAs; Treatment Outcome; Gene Expression Regulation; Blood-Brain Barrier; hippocampal sclerosis; Hippocampal sclerosis; Molecular Medicine; epileptogenesis; Original Article; RNA Interference; Disease Susceptibility; antisense oligonucleotides; Antiepileptic drug

Oligonucleotide therapies offer precision treatments for a variety of neurological diseases, including epilepsy, but their deployment is hampered by the blood-brain barrier (BBB). Previous studies showed that intracerebroventricular injection an antisense oligonucleotide (antagomir) targeting microRNA-134 (Ant-134) reduced evoked and spontaneous seizures in animal models epilepsy. In this study, we used assays serum protein tracer extravasation to determine BBB disruption occurring after status epilepticus mice was sufficient permit passage systemically injected Ant-134 into brain parenchyma. Intraperitoneal intravenous reached hippocampus blocked seizure-induced upregulation miR-134. A single intraperitoneal at 2 h resulted potent suppression recurrent seizures, reaching 99.5% reduction during recordings 3 months. The duration when they occurred, also Ant-134-treated mice. vivo knockdown LIM kinase-1 (Limk-1) increased seizure frequency mice, implicating de-repression Limk-1 antagomir mechanism. These indicate systemic delivery reaches produces long-lasting seizure-suppressive effects timed with may be clinically viable approach other disease-modifying microRNA therapies.