30RNA therapies such as oligonucleotides (OGNs) offer precision treatments for a variety of 31 neurological diseases, including epilepsy but their deployment is hampered by the blood brain 32 barrier (BBB). Here we used brain imaging and assays of serum proteins and tracer 33 extravasation, to determine that BBB disruption occurring after status epilepticus in mice was 34 sufficient to permit passage of systemically-injected antisense OGNs targeting microRNA-134 35 (Ant-134) into the brain parenchyma. A single intraperitoneal injection of Ant-134 two hours 36 after status epilepticus in mice resulted in potent suppression of spontaneous recurrent 37 seizures, reaching a 99.5% reduction during recordings at three months. The duration of 38 spontaneous seizures, when they occurred, was also reduced in Ant-134-treated mice. These 39 studies indicate that systemic delivery of Ant-134 reaches the brain and produces disease-40 modifying effects after systemic injection in mice when timed with BBB disruption and may be 41 a clinically-viable approach for this and other disease-modifying microRNA therapies. 42 43 44 45