To determine whether NTX-001 is efficacious and safe across a clinically relevant dosing range in a chronic mouse model of temporal lobe epilepsy (TLE).

Transplantation of medial ganglionic eminence (MGE) GABAergic interneurons into the brain and spinal cord has been shown to re-balance hyper-excitable neural networks and to be disease modifying in multiple rodent model studies. We are developing a clinical-grade interneuron cell therapy, NTX-001, derived from a human pluripotent stem cell line for prospective clinical investigation in patients with drug-resistant TLE. NTX-001 comprises an MGE-type cortical/hippocampal lineage of post-mitotic interneurons with >98% purity.  

NTX-001 was evaluated in the intra-hippocampal kainate chronic mouse model of TLE, which is a model for pharmacoresistant electrographic seizures and resembles many aspects of human TLE pathology. In the chronic epileptic stage, animals received multiple independent lots and doses of NTX-001, or vehicle control, via intra-hippocampal administration. We examined the mice for focal seizures by EEG, potential behavioral abnormalities, hippocampal pathology, and human cell engraftment for up to 10 months post-transplant (MPT). 

NTX-001 matured into appropriate interneuron subtypes, distributed throughout the epileptic mouse hippocampus, and stably persisted for the study duration. Overall, ~75% of mice that received cell-transplants became seizure-free by 6 MPT. Cell transplantation reproducibly led to stable seizure suppression with ~85% fewer electrographic seizures than vehicle control animals. The cumulative duration of focal seizures was also reduced. Hippocampal neurodegeneration and dentate dispersion were significantly decreased in the cell-treated mice. A dosing range was explored to identify candidate minimum-effective and maximum-feasible doses. In the dose escalation studies, no ectopic human tissues or teratomas were found, and no adverse behavioral effects were detected.

NTX-001 persisted in the epileptic mouse hippocampus, was well tolerated across a wide dosing range, and primarily resulted in stable seizure freedom. These findings support further development of NTX-001 for chronic TLE.