Systemic Delivery of Antagomirs During Blood-brain Barrier Disruption is Disease-modifying in Experimental Epilepsy

Overview

Journal Mol Ther

Publisher Cell Press

Specialties Molecular Biology
Pharmacology

Date 2021 Feb 20

PMID 33609732

Citations 16

Authors

Cristina R Reschke

Luiz F A Silva

Vamshidhar R Vangoor

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 Ruber

Jochen H M Prehn

Matthew Campbell

R Jeroen Pasterkamp

David C Henshall

Affiliations

Soon will be listed here.

Abstract

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

Citing Articles

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