Therapeutic Inhibition of microRNA-134 Potently Suppresses Spontaneous Recurrent Seizures in Mice with Pre-existing Drug-resistant Temporal Lobe Epilepsy
Abstract number :
3.472
Submission category :
8. Non-ASM/Non-Surgical Treatments (Hormonal, alternative, etc.)
Year :
2023
Submission ID :
1457
Source :
www.aesnet.org
Presentation date :
12/4/2023 12:00:00 AM
Published date :
Authors :
Presenting Author: Janine Erler, PhD – Neumirna Therapeutics
Stine Normann Hansen, PhD – Neumirna Therapeutics; Omar Mamad, PhD – RCSI; Lluis Riera Ponsati, PhD – Neumirna Therapeutics; Sakari Kauppinen, PhD – Aalborg University; David Henshall, PhD – RCSI; Henrik Klitgaard, PhD – Neumirna Therapeutics
Rationale: RNA-targeted medicines are an emerging class of innovative therapeutics with great potential for treatment of epilepsies. MicroRNA-134 (miR-134) has previously been identified as dysregulated in brain tissue in patients with drug-resistant temporal lobe epilepsy and targeting of miR-134 using chemically-modified antisense oligonucleotides (ASOs) was reported to reduce seizures in mouse models of epilepsy. Neumirna Therapeutics was founded in 2020 to develop disease-modifying RNA therapies for patients with drug-resistant epilepsy and other neurological disorders. Here, we report therapeutic inhibition of miR-134 deploying a design-optimized ASO lead candidate and explored whether this ASO can reduce spontaneous seizures in animals with pre-existing drug-resistant epilepsy.
Methods: We first used a miR-134 luciferase reporter and additional in vitro assays to screen a library of ASO compounds designed to target miR-134. The most potent ASO was subsequently advanced for in vivo testing in the mouse intra-amygdala kainic acid (IAKA) model.
Results: Our lead ASO showed potent knockdown of miR-134 in vitro and in vivo in naive mice. A single ICV injection of the ASO before IAKA reduced status epilepticus. Importantly, when the ASO was administered after the mice had developed chronic epilepsy there was a significant reduction in spontaneous seizures, beginning within a few days of administration and lasting until the end of recordings, two months later, showing unprecedented disease control.
Conclusions: We have identified a lead ASO candidate for disease-modifying RNA therapy for drug-resistant epilepsy. Preclinical studies exploring PK/PD, safety and tolerability of the lead ASO are under way.
Funding: Innovation Fund Denmark
Non-ASM