# Stem Cell-Derived Developmental Human Cortical Interneurons to Treat Intractable Epilepsy

> **NIH NIH R56** · NEW YORK MEDICAL COLLEGE · 2021 · $565,775

## Abstract

Abstract
Epilepsy is a severe neurological disease affecting more than 65 million people worldwide and is characterized
by unpredictable abnormal electrical discharges resulting in recurrent seizures. About one third of patients with
epilepsy suffer from intractable seizures that do not respond to antiepileptic drugs (AEDs). Neurosurgical
interventions and neurostimulator devices are useful options for only a fraction of patients with drug-refractory
seizures, underscoring the urgent need to develop new therapies. One strategy with considerable promise is to
engraft new neurons to provide enhanced GABAergic inhibition in an activity-dependent manner. However, use
of fetal neurons for cell therapy is associated with practical and ethical issues. Therefore, to overcome such
hurdles, in our previous studies, we pioneered the transplantation of human pluripotent stem cells (hPSCs)-
derived medial ganglionic eminence (MGE)-type human developmental cortical interneurons (cINs) into
epileptic mouse brains and demonstrated their integration into dysfunctional circuitry, accompanied by the
suppression of seizures and comorbid behavioral abnormalities. Furthermore, we have also determined the
optimal stage of human cIN differentiation to ensure maximal integration into host circuitry as well as safety
without risk of tumor formation, and developed a method to efficiently generate these safe and highly migratory
populations of cINs from hPSCs in large quantities, bringing cell therapy for epilepsy one step closer to reality.
However, there are still important issues to address prior to the clinical translation of this promising restorative
therapy; 1) what is the synaptic connection specificity of human developmental cINs in adult epileptic circuitry?
2) what are safe and optimal densities of human cIN grafts for inhibition of epileptic host circuitry? 3) do human
developmental cIN grafts maintain long-term efficacy and safety in epileptic brains? To tackle these issues, we
will test our hypothesis that human iPSC-derived developmental cINs with optimal grafting densities
preferentially innervate host excitatory neurons and ameliorate seizure activity with long-term efficacy and
safety. We will transplant migratory human cINs into Nod Scid gamma (NSG) mice with intrahippocampal
kainic acid-induced temporal lobe epilepsy (KA-TLE), a model of human hippocampal sclerosis, the most
common cause of drug-resistant epilepsy, and analyze grafted cINs’ synaptic integration specificity and host
inhibition in the epileptic brains. The long-term maintenance of anti-epileptic efficacy will be extensively
analyzed by 24/7 video-EEG recordings 3 months, 6 months and 9 months after transplantation. We will
analyze the grafts immunohistochemically to determine the extent of cell survival, maturation, integration, and
most importantly, cell proliferation as a measure of graft safety without risk of uncontrolled growth. Completion
of these studies is pivotal for translating t...

## Key facts

- **NIH application ID:** 10355921
- **Project number:** 1R56NS121541-01
- **Recipient organization:** NEW YORK MEDICAL COLLEGE
- **Principal Investigator:** SANGMI CHUNG
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $565,775
- **Award type:** 1
- **Project period:** 2021-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10355921

## Citation

> US National Institutes of Health, RePORTER application 10355921, Stem Cell-Derived Developmental Human Cortical Interneurons to Treat Intractable Epilepsy (1R56NS121541-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10355921. Licensed CC0.

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