Senior Scientist Neurona Therapeutics Inc. South San Francisco, California
This abstract has been invited to present during the Investigators Workshop Platform poster session
Rationale: Transplantation of medial ganglionic eminence (MGE) forebrain-type GABAergic interneurons into the brain and spinal cord has been shown to restore balance to hyper-excitable neural networks in preclinical rodent models. We are developing a human MGE-type interneuron cell therapy, NTX-001 derived from a human pluripotent stem cell (hPSC) line, for clinical investigation in patients with drug-resistant temporal lobe epilepsy (TLE). The human cell therapy can be reproducibly manufactured to derive post-mitotic interneurons from hPSCs with >85% efficiency. NTX-001 cells express markers of an MGE-type cortical/hippocampal interneuron lineage. Methods: The efficacy of NTX-001 human interneurons was evaluated after transplantation into the intra-hippocampal kainate mouse model of mesial TLE, which is a model for pharmacoresistant seizures and resembles many aspects of human TLE pathology. Following kainate-induced status epilepticus, mice developed spontaneous recurrent electrographic seizures. In this chronic epileptic stage, animals received hippocampal transplants of NTX-001, or control injections of vehicle. Mice were monitored for seizures with hippocampal electrodes at several time points for up to 10 months post-transplant (PT) and cell persistence, fate and distribution were evaluated at the end of the study. We compared different production batches of NTX-001 as well as different doses to identify a minimally efficacious dose and maximum feasible dose, which included multiple behavioral assays to detect potential abnormalities. Additionally, we assessed hippocampal pathology by scoring neurodegeneration and measuring the extent of granule cell dispersion. Results: NTX-001 matured into interneuron subtypes, which were distributed throughout the epileptic mouse hippocampus, and the human interneurons persisted for at least one year PT, the latest time point studied. Transplantation reproducibly led to long-term seizure suppression with 70-80% fewer electrographic seizures in the mice that received cell transplants than in age-matched vehicle-injected mice across multiple studies and cell batches of NTX-001. The cumulative duration of seizures was also reduced significantly. Overall, two-thirds of mice that received cell-transplants became seizure-free by 6 months PT. The most severe neurodegeneration and granule cell dispersion in this model is found close to the kainate injection site in the ipsilateral rostral CA1. Pathology was significantly alleviated in the rostral hippocampus in the mice that were transplanted with cells. Transplants with a 7.5x higher dose also decreased damage in less affected areas caudal from the kainate injection site. The higher doses of NTX-001 resulted in comparable seizure suppression to the lower reference dose studies.In the dose escalation studies, no ectopic human tissues or teratomas were found and no adverse effects were detected across a battery of behavioral assays with up to a 25x higher dose. Conclusions: NTX-001 human interneurons persist long-term in the epileptic mouse hippocampus, result in stable seizure freedom and reduce hippocampal pathology for most animals, and are well tolerated at high doses. These findings support further development of inhibitory interneuron cell therapy for drug-resistant TLE. Funding: Please list any funding that was received in support of this abstract.: This research was supported in part by a grant from the California Institute for Regenerative Medicine (CIRM DISC2-10525; TRAN1-11611).