Human cortical interneurons optimized for grafting specifically integrate, abort seizures, and display prolonged efficacy without over-inhibition
Summary
Previously, we demonstrated the efficacy of human pluripotent stem cell (hPSC)-derived GABAergic cortical interneuron (cIN) grafts in ameliorating seizures. However, a safe and reliable clinical translation requires a mechanistic understanding of graft function, as well as the assurance of long-term efficacy and safety. By employing hPSC-derived chemically matured migratory cINs in two models of epilepsy, we demonstrate lasting efficacy in treating seizures and comorbid deficits, as well as safety without uncontrolled growth. Host inhibition does not increase with increasing grafted cIN densities, assuring their safety without the risk of over-inhibition. Furthermore, their closed-loop optogenetic activation aborted seizure activity, revealing mechanisms of graft-mediated seizure control and allowing graft modulation for optimal translation. Monosynaptic tracing shows their extensive and specific synaptic connections with host neurons, resembling developmental connection specificity. These results offer confidence in stem cell-based therapy for epilepsy as a safe and reliable treatment for patients suffering from intractable epilepsy. Copyright © 2022 Elsevier Inc. All rights reserved.
| Authors | Zhu Q, Mishra A, Park JS, Liu D, Le DT, Gonzalez SZ, Anderson-Crannage M, Park JM, Park GH, Tarbay L, Daneshvar K, Brandenburg M, Signoretti C, Zinski A, Gardner EJ, Zheng KL, Abani CP, Hu C, Beaudreault CP, Zhang XL, Stanton PK, Cho JH, Velíšek L, Velíšková J, Javed S, Leonard CS, Kim HY, Chung S |
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| Journal | Neuron |
| Publication Date | 2023 Mar 15;111(6):807-823.e7 |
| PubMed | 36626901 |
| PubMed Central | PMC10023356 |
| DOI | 10.1016/j.neuron.2022.12.014 |