NRTX-1001: First-in-class Human Inhibitory Neuron Cell Therapy for Phase I/II Clinical Investigation in Chronic Focal Epilepsy
Abstract number :
3.102
Submission category :
2. Translational Research / 2B. Devices, Technologies, Stem Cells
Year :
2022
Submission ID :
2204422
Source :
www.aesnet.org
Presentation date :
12/5/2022 12:00:00 PM
Published date :
Nov 22, 2022, 05:24 AM
Authors :
David Blum, MD – Neurona Therapeutics; Mansi Parekh, PhD – Neurona Therapeutics; Philip Hampel, PhD – Neurona Therapeutics; Hannah Kim, PhD – Neurona Therapeutics; Eric Sevilla, PhD – Neurona Therapeutics; Andrew Adler, PhD – Neurona Therapeutics; Brianna Feld, PhD – Neurona Therapeutics; Nathalie Picard, PhD – Neurona Therapeutics; Seonok Lee, PhD – Neurona Therapeutics; Ji-Hye Jung, PhD – Neurona Therapeutics; Michael Watson, PhD – Neurona Therapeutics; Steven Havlicek, PhD – Neurona Therapeutics; Marina Bershteyn, PhD – Neurona Therapeutics; Yves Maury, PhD – Neurona Therapeutics; Geetha Subramanyam, PhD – Neurona Therapeutics; Meliz Sezan, PhD – Neurona Therapeutics; Verginia Carlson, PhD – Oregon National Primate Research Center; Kim Burchiel, MD – Oregon Health and Science University; Myriam Chaumeil, PhD – U.California San Francisco; Marina Radoul, PhD – U.California San Francisco; Alessandro Bulfone, MD – 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 pharmacoresistant seizures. Surgical resection or ablation of a seizure focus can be an effective treatment option for chronic focal epilepsy; however, these options are tissue-destructive and are not indicated for all. As a 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. A phase I/II clinical trial (NCT05135091) has been launched to evaluate NRTX-1001 in people with pharmacoresistant temporal lobe epilepsy (TLE).
Methods: Clinically-compliant processes were used to reliably manufacture and cryopreserve NRTX‑1001, with assessments of composition, neuronal migration, GABA release, sterility, and viability. Preclinical studies included functional assessments of the cells in a rodent model of chronic pharmacoresistant focal seizures, behavioral assessments in implanted rodents, and MRI-guided delivery into the non-human primate hippocampus using a clinical-grade stereotactic delivery system. In addition, magnetic resonance spectroscopy (MRS) was used to assess local tissue metabolic profiles that suggest potential non-invasive biomarkers of NRTX-1001 activity. The clinical trial design includes an open-label dose escalation in up to 10 subjects, followed by a randomized controlled investigation, compared to a sham control group, to evaluate NRTX-1001 safety and efficacy in up to 30 subjects.
Results: A single intrahippocampal administration of NRTX-1001 into mice with chronic mesiotemporal seizures induced by kainic acid led to hippocampal distribution and persistence of the implanted interneurons, and resulted in pronounced focal seizure reduction and reduced hippocampal pathology. Approximately two-thirds of epileptic mice were stably seizure-free after receiving intrahippocampal implantation of NRTX-1001. MRS identified levels of select metabolites that were altered in the epileptic hippocampus and partially normalized post-administration of NRTX-1001. On a behavior assessment panel, interneuron-implanted rodents showed no adverse behavioral effects. Intrahippocampal delivery, distribution, and persistence of NRTX-1001 for at least 3 months post-implantation were demonstrated in immunosuppressed non-human primates.
Conclusions: The results of these preclinical studies support the ongoing phase I/II clinical trial to assess the safety and preliminary efficacy of NRTX-1001 in people with pharmacoresistant TLE. An update from the clinical trial will also be presented.
Funding: CIRM (TRAN1-11611, CLIN2-13355)
Translational Research