Authors :
Presenting Author: Janine Erler, PhD – Neumirna Therapeutics
Lluis Riera Ponsati, PhD – Neumirna Therapeutics
Omar Mamad, PhD – RCSI
Jordan Higgins, PhD – RCSI
Sakari Kauppinen, PhD – Neumirna Therapeutics
David Henshall, PhD – RCSI
Henrik Klitgaard, PhD – Neumirna Therapeutics
Rationale:
Drug-resistant epilepsy (DRE) affects over 30% of individuals with focal epilepsy and is frequently accompanied by psychiatric and cognitive comorbidities such as anxiety, depression, and memory impairment. Current anti-seizure medications (ASMs) offer symptomatic relief but do not address the underlying pathophysiology or the broad comorbidity spectrum of epilepsy. The brain-enriched microRNA miR-134 is upregulated in temporal lobe epilepsy (TLE), and inhibition of miR-134 using antisense oligonucleotides (ASOs) has shown potent seizure-suppressive and antiepileptogenic effects in preclinical models. However, its effect on epilepsy-related comorbidities remains underexplored. This study investigates whether NMT.001, a proprietary anti-miR-134 ASO developed by Neumirna Therapeutics, can also ameliorate behavioral impairments in a mouse model of DRE.
Methods:
We utilized the intra-amygdala kainic acid (IAKA) model of TLE in mice, which recapitulates key features of DRE including behavioral comorbidities. Mice were stereotactically injected with KA or PBS, followed by lorazepam to abort status epilepticus. On Day 14 post-KA, mice received an intracerebroventricular (ICV) injection of 1 nmol NMT.001 or vehicle. Behavioral testing was conducted at baseline, pre-treatment, and at two timepoints post-treatment (Day 23 and Day 64). Tests included open field (locomotion), marble burying (anxiety-related/exploratory behavior) and novel object recognition (cognition).
Results:
Mice with KA-induced epilepsy exhibited increased locomotion, impaired recognition memory, and reduced marble burying behavior—indicative of anxiety-like and cognitive symptoms. A single administration of NMT.001 was able to rescue several the following KA-induced behavioral deficits:
- Open field: KA-treated mice showed hyperactivity, which was attenuated after NMT.001 administration.
- Novel object recognition: KA/PBS mice displayed a reduced discrimination index, whereas KA/NMT.001 mice performed similarly to controls, suggesting preserved recognition memory.
- Marble burying: KA/PBS mice buried significantly fewer marbles; NMT.001 reversed this deficit, with recovery sustained at both early (Day 23) and late (Day 64) readouts (p < 0.001