Potent and lasting seizure suppression by systemic delivery of antagomirs targeting miR-134 timed with blood-brain barrier disruption
Reschke, C. R.; Almeida Silva, L. F.; Vangoor, V. R.; Rosso, M.; David, B.; Cavanagh, B.; Connolly, N. M. C.; Brennan, G. P.; Sanz-Rodriguez, A.; Mooney, C.; Batool, A.; Greene, C.; Brennan, M.; Conroy, R. M.; Ruber, T.; Prehn, J.; Campbell, M.; Pasterkamp, R. J.; Henshall, D. C.
Show abstract
RNA therapies such as oligonucleotides (OGNs) offer precision treatments for a variety of neurological diseases, including epilepsy but their deployment is hampered by the blood brain barrier (BBB). Here we used brain imaging and assays of serum proteins and tracer extravasation, to determine that BBB disruption occurring after status epilepticus in mice was sufficient to permit passage of systemically-injected antisense OGNs targeting microRNA-134 (Ant-134) into the brain parenchyma. A single intraperitoneal injection of Ant-134 two hours after status epilepticus in mice resulted in potent suppression of spontaneous recurrent seizures, reaching a 99.5% reduction during recordings at three months. The duration of spontaneous seizures, when they occurred, was also reduced in Ant-134-treated mice. These studies indicate that systemic delivery of Ant-134 reaches the brain and produces disease-modifying 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.
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