NRTX-1001: Human Inhibitory Neuron Cell Therapy Suppresses Seizures and Reduces Histopathology in Mouse Model of Chronic Epilepsy with High Repeatability Across Multiple Studies and Manufacturing Lots
Abstract number :
1.277
Submission category :
7. Anti-seizure Medications / 7A. Animal Studies
Year :
2022
Submission ID :
2204360
Source :
www.aesnet.org
Presentation date :
12/3/2022 12:00:00 PM
Published date :
Nov 22, 2022, 05:24 AM
Authors :
Philip Hampel, DVM, PhD – Neurona Therapeutics; Mansi Parekh, PhD – Neurona Therapeutics; Hannah Kim, PhD – Neurona Therapeutics; Eric Steven Sevilla, BS – Neurona Therapeutics; Fiona Porkka, BA – Neurona Therapeutics; Alexandra Vogel, MS – Neurona Therapeutics; Seonok Lee, PhD – Neurona Therapeutics; Ji-Hye Jung, PhD – Neurona Therapeutics; Nathalie Picard, PhD – Neurona Therapeutics; Michael Watson, PhD – Neurona Therapeutics; Steven Havlicek, PhD – Neurona Therapeutics; Marina Bershteyn, PhD – Neurona Therapeutics; Yves Maury, PhD – Neurona Therapeutics; David Blum, MD, PhD – Neurona Therapeutics; Alessandro Bulfone, MD, PhD – Neurona Therapeutics; Gautam Banik, PhD – Neurona Therapeutics; Catherine Priest, PhD – Neurona Therapeutics; Cory Nicholas, PhD – Neurona Therapeutics
Rationale: One-third of people with epilepsy have drug-resistant seizures. Surgical resection or ablation of a seizure focus can be effective options for chronic focal epilepsy; however, these procedures are tissue-destructive and are not indicated for all. As a restorative therapeutic alternative, the administration of cells that deliver GABA to the seizure focus could suppress chronic seizures without tissue destruction. NRTX‑1001 comprises GABAergic, post-mitotic interneurons of a specific pallial-type lineage derived from human pluripotent stem cells. This contribution examines the repeatability of NRTX-1001 transplantation to affect endpoints of seizure suppression and histopathology in preclinical studies.
Methods: Clinically-compliant processes were used to reliably manufacture and cryopreserve NRTX‑1001. Multiple preclinical studies were performed in the intrahippocampal kainate mouse model of drug-resistant focal epilepsy using independent manufacturing lots of NRTX-1001. Single intrahippocampal administration of NRTX-1001 was performed in the chronic phase of the disease model, which is characterized by spontaneous recurrent seizures and hippocampal sclerosis. Focal seizures were detected by continuous EEG recording from bipolar hippocampal electrodes at several timepoints up to 7 months post transplantation, and behavioral testing assessed cognitive function and health. At 7.5 months post transplantation of NRTX-1001, cell engraftment and hippocampal histopathology were assessed.
Results: A single intrahippocampal administration of NRTX-1001 into mice with chronic mesiotemporal seizures induced by kainic acid resulted in pronounced reduction of focal seizures across multiple independent cell lots and studies. NRTX-1001 transplantation consistently resulted in stable seizure-freedom in approximately two-thirds of epileptic mice and produced no adverse behavioral effects. NRTX-1001 interneurons persisted for the duration of the studies, distributed throughout the hippocampus, and reduced hippocampal neurodegeneration and granule cell dispersion. No ectopic tissues, tumors or teratomas were observed following transplantation of NRTX-1001.
Conclusions: The results of these preclinical studies support the ongoing phase I/II clinical trial (NCT05135091) to evaluate NRTX-1001 in people with drug-resistant temporal lobe epilepsy.
Funding: CIRM (TRAN1-11611, CLIN2-13355)
Anti-seizure Medications