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Full text release has been delayed at the author's request until May 17, 2026

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HARNESSING THE POWER OF STEM CELL TECHNOLOGIES IN EPILEPSY RESEARCH - FROM DISEASE MODELING TO DRUG DISCOVERY

Ahn, Lucie Yeongran
http://orcid.org/0000-0001-8485-3788
http://rave.ohiolink.edu/etdc/view?acc_num=case1712231003993096

Abstract Details

2024, Doctor of Philosophy, Case Western Reserve University, Genetics.
Epilepsy is a neurological disorder characterized by repeated seizures. It affects 1% of the US population. Despite the recent progress in antiepileptic drug discovery and development, approximately 30% of the patients do not respond to current therapies. A major pitfall of the current antiepileptic drug discovery pipeline is current animal seizure models. The most widely used animal models are mechanically or chemically induced models, and they fail to recapitulate drug-resistant seizures, which are largely genetic epilepsies. Induced pluripotent stem cells (iPSCs) are promising alternative preclinical epilepsy models. iPSCs preserve the genetic information of epilepsy patients and can be an unlimited source of neuronal cell types of interest. Many studies have shown that iPSC disease models successfully reproduce epilepsy phenotypes. Herein, we successfully leveraged stem cell reprogramming technologies and CRISPR/Cas9 gene editing tools to generate iPSCs models of three drug-resistant epilepsies with monogenic cause: Early infantile epileptic encephalopathy, subtype 76 (EIEE-76), Microcephaly, Epilepsy, Diabetes Syndrome (MEDS), and GRIN2A-related epilepsy. Using these models, we uncovered pathophysiological mechanisms underlying the epilepsy phenotype of these rare genetic epilepsies that were previously unknown. We demonstrated EIEE-76 patient variant of ACTL6B dysregulates genes essential for neuronal development and that EIEE-76 patient-derived neurons demonstrated elevated electrophysiological activity than control, consistent with the patient phenotype. Also, we elucidated MEDS patient-derived neural progenitor cells (NPCs) have defects in secretory protein trafficking. Impaired protein trafficking during neurogenesis resulted in abnormal neuronal differentiation and electrophysiologically less active neuronal population. Next, we took a step further and developed a disease-relevant, high-throughput, phenotypic screen platform to identify potential antiepileptic therapeutics that can improve protein trafficking with MEDS patient-derived NPCs. From the phenotypic screen, we discovered that FDA-approved CFTR correctors enhance protein trafficking. Excitingly, CFTR correctors restored reduced neuronal activity in MEDS patient-derived neuronal cultures and the GRIN2A-related epilepsy model. Our results confirm that genetic epilepsy patient-derived iPSCs could be utilized to develop a disease-relevant drug screening platform and to discover novel antiepileptic therapies. Collectively, our work proves that patient-derived iPSCs-based models of epilepsy can be used to deepen our understanding of disease mechanisms and to identify novel antiepileptic therapies.
Ashleigh Schaffer (Advisor)
Yan Li (Committee Member)
Drew Adams (Committee Chair)
Anthony Wynshaw-Boris (Committee Member)
Andrew Pieper (Committee Member)
150 p.
Genetics
Epilepsy, Stem cell, Rare disease, MEDS, GRIN2A, Genetics, Cell Biology, Neuroscience, Drug Screen, Drug Discovery

Recommended Citations

Citations

  • Ahn, L. Y. (2024). HARNESSING THE POWER OF STEM CELL TECHNOLOGIES IN EPILEPSY RESEARCH - FROM DISEASE MODELING TO DRUG DISCOVERY [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1712231003993096

    APA Style (7th edition)

  • Ahn, Lucie. HARNESSING THE POWER OF STEM CELL TECHNOLOGIES IN EPILEPSY RESEARCH - FROM DISEASE MODELING TO DRUG DISCOVERY. 2024. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1712231003993096.

    MLA Style (8th edition)

  • Ahn, Lucie. "HARNESSING THE POWER OF STEM CELL TECHNOLOGIES IN EPILEPSY RESEARCH - FROM DISEASE MODELING TO DRUG DISCOVERY." Doctoral dissertation, Case Western Reserve University, 2024. http://rave.ohiolink.edu/etdc/view?acc_num=case1712231003993096

    Chicago Manual of Style (17th edition)

case1712231003993096
© 2024, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.