Abstracts

Rationale: At least one-third of people with epilepsy have seizures that are drug-resistant. Anti-seizure drugs that potentiate the inhibitory neurotransmitter GABA provide potent seizure suppression, but their use is limited by the development of side effects, tolerance, and the potential for abuse. Surgical resection or ablation of a seizure focus can be an effective option for chronic focal-onset epilepsy, however these options are tissue-destructive and are not indicated for all individuals. A cellular therapeutic delivering GABA to focal regions of seizure onset could restore balanced neural activity and suppress chronic seizures without destruction of tissue. Development of a cellular therapeutic for clinical use requires reliable manufacturing and thorough characterization of the cell product, comprehensive testing in preclinical models, and tailored design of clinical trials that assess the safety and benefit of the therapy in appropriate patient populations.

Methods: Clinically-compliant processes were used to consistently manufacture and cryopreserve a post-mitotic GABAergic interneuron product candidate, NRTX-1001, derived from a human pluripotent stem cell line. NRTX-1001 was characterized for composition, sterility, viability, and the lack of adventitious agents. Preclinical studies included functional assessments in a rodent model of chronic pharmacoresistant focal seizures; extensive safety testing to assess biodistribution, toxicology and tumorigenicity; and MRI-guided delivery into non-human primates.

Results: Administration of NRTX-1001 was well-tolerated in preclinical models across a wide dosing range. Hippocampal administration of NRTX-1001 into mice with intrahippocampal kainic acid-induced chronic mesiotemporal seizures resulted in pronounced focal seizure reduction, hippocampal distribution and persistence of transplanted interneurons, and reduced hippocampal pathology. Approximately 75% of epileptic mice were stably seizure-free after receiving NRTX-1001, as compared to 8% of animals in the control group. Biodistribution studies with histological and qPCR-based analyses of central and peripheral tissues confirmed that cell persistence was restricted to the hippocampus. Daily clinical observations and assessments of histopathology, hematology and clinical chemistries at multiple time points post-transplantation did not indicate systemic toxicities or adverse behavioral effects related to NRTX-1001. Targeted intrahippocampal delivery, engraftment, and persistence of NRTX-1001 were demonstrated in immunosuppressed non-human primates. No ectopic tissues or teratomas were found after transplantation of NRTX-1001 in any preclinical model.

Conclusions: The results of these studies will be submitted as part of an Investigational New Drug (IND) application to the FDA to support a Phase 1/2a clinical trial to assess the safety and preliminary efficacy of NRTX-1001 in patients with drug-resistant mesiotemporal lobe epilepsy. The proposed clinical trial design will be presented.

Funding: Please list any funding that was received in support of this abstract.: CIRM (TRAN1-11611).