Abstract Details

Title Preclinical Development of NRTX-1001, an Inhibitory Interneuron Cellular Therapeutic for the Treatment of Chronic Focal Epilepsy

Topic Epilepsy/Clinical Neurophysiology (EEG)

Presentation(s) S13 - Epilepsy/Clinical Neurophysiology (EEG): Antiseizure Medications (2:12 PM-2:24 PM)

Poster/Presentation
Number 007

Objective

· Investigate mesiotemporal seizure frequency, sclerosis, and metabolic changes after NRTX-1001 transplantation into a chronic mouse model of temporal lobe epilepsy (TLE).

· Assess NRTX-1001 effectiveness in the presence of the anti-seizure drug levetiracetam.

Background One-third of people with epilepsy have drug-resistant seizures. For drug-resistant focal TLE, a cellular therapeutic targeted to the temporal lobe could potentially restore balanced neural activity, avoid unwanted effects common to anti-seizure drugs, and provide an alternative to tissue-destructive resection/ablation surgeries. NRTX-1001 is a clinical-grade cellular therapeutic comprised of post-mitotic GABAergic interneurons of a pallial-type lineage derived from human pluripotent stem cells.

Design/Methods NRTX-1001 transplantation was evaluated in the chronic phase of the intrahippocampal kainate mouse model of TLE. Animals receiving intrahippocampal NRTX-1001 or vehicle were treated with levetiracetam or saline, and examined for electrographic seizures, potential behavioral abnormalities, hippocampal pathology, and human cell engraftment for up to 12 months post-transplant (MPT). Metabolic alterations were monitored non-invasively using ¹H magnetic resonance spectroscopy. Hippocampal volume was measured using anatomical T₂-weighted MRI.

Results Administration of NRTX-1001 resulted in pronounced focal seizure reduction, reduced hippocampal pathology, and decreased dentate granule cell dispersion in the TLE model. NRTX-1001 transplantation led to more epileptic animals surviving to 7 MPT, and ~ 50% were stably seizure-free, which was not observed in controls. Animals remained seizure-free after acute treatment with levetiracetam. No ectopic tissues, teratomas or behavioral deficits were observed. Significant MR-detectable metabolic alterations were observed in epileptic mice, which were restored towards control levels post-NRTX-1001 transplant.

Conclusions NRTX-1001 cells persisted in the epileptic mouse hippocampus, were well- tolerated, and resulted in stable seizure suppression. Combining levetiracetam and NRTX-1001 maintained the anti-seizure effect. MRS detected metabolic modulations that could be used as potential clinical biomarkers of seizure reduction following NRTX-1001 administration. These findings support further development of NRTX-1001 for chronic focal epilepsy.

Authors/Disclosures
Mansi B. Parekh, PhD (Neurona Therapeutics) PRESENTER	Dr. Parekh has received personal compensation for serving as an employee of Neurona Therapeutics.
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
Luis Fuentealba (Neurona Therapeutics)	Luis Fuentealba has nothing to disclose.
	No disclosure on file
	No disclosure on file
	No disclosure on file
Marina Bershteyn (Neurona therapeutics)	Marina Bershteyn has received personal compensation for serving as an employee of Neurona therapeutics. Marina Bershteyn has stock in Neurona therapeutics. Marina Bershteyn has received intellectual property interests from a discovery or technology relating to health care.
Yves Maury (Neurona therapeutics)	Yves Maury has received personal compensation for serving as an employee of Neurona Therapeutics. Yves Maury has stock in Neurona therapeutics.
	No disclosure on file
Catherine Priest, PhD (Neurona Therapeutics, Inc)	Catherine Priest has received personal compensation for serving as an employee of Neurona Therapeutics. Catherine Priest has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Novo Nordisk. The institution of Catherine Priest has received research support from CIRM.
Cory R. Nicholas, PhD (Neurona Therapeutics)	Dr. Nicholas has received personal compensation for serving as an employee of Neurona Therapeutics. Dr. Nicholas has stock in Neurona Therapeutics. Dr. Nicholas has received intellectual property interests from a discovery or technology relating to health care.

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