NRTX-1001 Shows Seizure Suppression in Preclinical Drug-Resistant Focal Epilepsy Models


Neurona Therapeutics’ NRTX-1001, a regenerative neural cell therapy derived from human stem cells, showed promise in potentially suppressing seizures in patients with drug-resistant mesial temporal lobe epilepsy.

Cory R. Nicholas, PhD, chief executive officer at Neurona Therapeutics

Cory R. Nicholas, PhD

In preclinical data recently published in Cell Stem Cell, administration of a single dose of NRTX-1001 (Neurona Therapeutics), a regenerative neural cell therapy candidate derived from human pluripotent stem cells, demonstrated a resistant and stable suppression of focal seizures in a chronic model of drug-resistant mesial temporal lobe epilepsy (MTLE). These findings support the development of the agent, which is currently being assessed in the ongoing phase 1/2 NTE001 trial (NCT05135091), as a potential treatment for patients living with focal epilepsy.1,2

In the mouse models, a single dose intrahippocampal delivery of the interneurons showed consistent mesiotemporal seizure suppression and thus, most animals became seizure-free and survived longer. Notably, the grafted interneurons dispersed locally, functionally integrated, and persisted long-term in the sclerotic hippocampus during the 8.5-month study. Additionally, in these models, the hippocampal dentate granule cell dispersion, a pathological hallmark of MTLE, was reduced significantly. The disease-modifying effects established in the study were dose-dependent, having a broad therapeutic range, and had no adverse events observed.

Clinical Takeaways

  • NRTX-1001, a neural cell therapy derived from human pluripotent stem cells, shows promising results in suppressing focal seizures in chronic drug-resistant mesial temporal lobe epilepsy.
  • Human stem cell-derived interneurons demonstrate sustained seizure suppression, long-term integration, and functional improvement in mouse models.
  • The findings show the potential of human inhibitory interneuron cell therapy as a functional and nondestructive alternative to surgical procedures for drug-resistant focal epilepsy.

“We developed a clinically-compatible, reproducible method to derive a pure population of cortical inhibitory interneurons of an MGE-type sublineage from human pluripotent stem cells. The identity of the derived interneurons was validated by lineage-specific marker expression, single-cell transcriptomics, migration, and GABA secretion, with high-fidelity to endogenous human cortical interneurons. The hESC-derived interneurons were transplanted into the mouse brain and shown to functionally integrate and persist long-term, fire action potentials, form synapses, and inhibit host neurons,” Cory R. Nicholas, PhD, chief executive officer at Neurona Therapeutics, told NeurologyLive®.

The human stem cell-derived pallial MGE-type, GABAergic interneurons were generated using a proprietary GMP-compliant manufacturing protocol, and the cells underwent extensive molecular and functional characterization including single-cell RNA sequencing, in vitro migration, and GABA secretion analyses. Following transplantation into the chronic intrahippocampal kainate model of MTLE, the human interneurons were analyzed for cellular migration and persistence, graft composition, synaptic connectivity, and dose-dependent reduction of seizure activity.

"When transplanted into the hippocampus in a mouse model of chronic mesial temporal lobe epilepsy, the human interneurons significantly suppressed mesiotemporal seizures in a dose-dependent manner for the lifespan of the animals from a single administration of cells," Nicholas told. "Surprisingly, we did not detect adverse behavioral effects of the human interneurons, such as sedation or memory impairment. Encouragingly, the grafted human interneurons resulted in reduced damage to the dentate gyrus, improved learning/memory, and increased survival of the epileptic animals."

READ MORE: Study Reveals Association Between Amygdala Region and Persistent Breathing Loss Following Seizures

The ongoing NTE001 trial is currently investigating the safety and efficacy of a single administration of NRTX-1001 among patients with drug-resistant MTLE from epilepsy centers in the US. The first stage of the study is an open-label dose-escalation study in up to 10 patients with MTLE, with 5 patients to be treated at a starting dose and 5 patients to be treated at a higher dose. The participants treated with a single infusion of NRTX-1001 cells will be observed for safety, tolerability, and effects on their symptoms of epilepsy.

“Human inhibitory interneuron cell therapy may represent an alternative to surgical lobectomy and ablation for people with drug-resistant focal epilepsy. Cell therapy has the potential to be functionally restorative to brain function in contrast to surgical resection/ablation, which is destructive to brain tissue and can cause neurocognitive impairment. Additionally, many patients are not eligible for surgical lobectomy or laser ablation,” Nicholas told.

In recent news, the first of 2 patients to be treated with NRTX-1001, who are now off the immunosuppression regimen, maintained a greater than 95% seizure reduction as of 16 months posttreatment, with no serious adverse effects detected thus far.3 Coming into the study, these patients had a history of significant monthly seizure activity that was not managed by antiseizure medications. The first patient had a 7-year history of seizures and, in the 6 months prior to the administration of NRTX-1001, experienced an average of 32 seizures per month. The second patient had a 9-year history of seizures and averaged 14 seizures per month in the 6 months prior to treatment. Both patients initiated neurocognitive testing 6 months posttreatment where specific neurocognitive scores increased from baseline levels. The company noted that these findings so far highlight the restorative potential of NRTX-1001 among patients with epilepsy.2

“This research supports an ongoing open label first-in-human phase 1/2 trial of NRTX-1001 interneuron cell therapy in 10 adults with drug-resistant mesial temporal lobe epilepsy. The first 5 participants at the starting dose-level have been treated, and NRTX-1001 has been well-tolerated to date. The first 2 participants in the study have reached the 1-year endpoint and have reported at least 95% seizure reduction from baseline. The data from all 5 participants will be presented at the AES meeting in December. The next 5 participants will be treated at the higher dose-level in 2024,” Nicholas told.

1. Bershteyn M, Bröer S, Parekh M, et al. Human pallial MGE-type GABAergic interneuron cell therapy for chronic focal epilepsy. Cell Stem Cell. 2023;30(10):1331-1350.e11. doi:10.1016/j.stem.2023.08.013
2. Neurona Therapeutics Announces Publication in Cell Stem Cell Reporting the Development of Investigational Novel Regenerative Cell Therapy Strategy for Drug-resistant Focal Epilepsy. News Release. Neurona Therapeutics. Published October 5, 2023. Accessed November 27, 2023.
3. Neurona Therapeutics completes clinical enrollment of first cohort and updates on long-lasting impact in first patients treated in ongoing phase I/ii trial of NRTX-1001 cell therapy for drug-resistant focal epilepsy. News release. Neurona Therapeutics. October 19, 2023. Accessed November 27, 2023.
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