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

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posted on 26.05.2021, 16:10 by Cristina Ruedell Reschke, Luiz FA Silva, Vamshidhar R Vangoor, Massimo Rosso, Bastian David, Brenton Cavanagh, Niamh Connolly, Gary P Brennan, Amaya Sanz Rodriguez, Catherine Mooney, Aasia Batool, Chris Greene, Marian Brennan, Ronan Conroy, Theodor Rüber, Jochen Prehn, Matthew Campbell, R Jeroen Pasterkamp, David Henshall
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

Funding

Science Foundation Ireland (SFI) under grant no. 16/RC/3948

Health Research Board Ireland (HRA-POR-2013-325)

Science Foundation Ireland (13/IA/1891 and 11/TIDA/B1988; 17/TIDA/5002; SFI/14/ADV/RC2721)

Brazilian National Council for Scientific and Technological Development (CNPq)

Dutch Epilepsiefonds (WAR 12-08 and WAR 15-05)

Irish Research Council

CURE Epilepsy

European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 602130 (EpimiRNA)

European Regional Development Fund

FutureNeuro industry partners

History

Comments

The original article is available at https://www.cell.com

Published Citation

Reschke CR, Silva LFA, Vangoor VR, Rosso M, David B, Cavanagh BL, Connolly NMC, Brennan GP, Sanz-Rodriguez A, Mooney C, Batool A, Greene C, Brennan M, Conroy RM, Rüber T, Prehn JHM, Campbell M, Pasterkamp RJ, Henshall DC. Systemic delivery of antagomirs during blood-brain barrier disruption is disease-modifying in experimental epilepsy. Mol Ther. 2021 Feb 18:S1525-0016(21)00088-5.

Publication Date

17 February 2021

PubMed ID

33609732

Department/Unit

  • FutureNeuro Centre
  • Physiology and Medical Physics
  • Public Health and Epidemiology
  • School of Pharmacy and Biomolecular Sciences

Publisher

Elsevier BV

Version

  • Published Version (Version of Record)