Human cortical interneurons optimized for grafting specifically integrate, abort seizures, and display prolonged efficacy without over-inhibition

Zhu, Qian; Mishra, Akanksha; Park, Joy S.; Liu, Dongxin; Le, Derek T; Gonzalez, Sasha Z; Anderson-Crannage, Morgan; Park, James M.; Park, Ho‐Jin; Tarbay, Laura; Daneshvar, Kamron; Brandenburg, Matthew; Signoretti, Christina; Zinski, Amy L.; Gardner, Edward-James; Zheng, Kelvin; Abani, Chiderah P; Hu, Carla; Beaudreault, Cameron; Zhang, Xiaolei; Stanton, Patric K.; Cho, Jun‐Hyeong; Velı́šek, Libor; Velı́šková, Jana; Javed, Saqlain; Leonard, Christopher; Kim, Hae-Young; Chung, Sangmi

doi:10.1016/j.neuron.2022.12.014

Cited by 11 publications

(4 citation statements)

References 76 publications

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“…Similarly, in the cortical area, parvalbumin-positive, fast-spiking basket cells play a crucial role in cortical inhibition. Supporting this is successful engraftment and seizure reduction following transplantation of human cortical interneurons in recent research [ 15 ], highlighting the critical importance of inhibitory actions in controlling seizures and epilepsy.…”

Section: Disinhibitionmentioning

confidence: 99%

Understanding epileptogenesis from molecules to network alteration

Park

2024

encephalitis

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Epilepsy is characterized by recurrent seizures. Following an initial insult, a latent period precedes the onset of spontaneous seizures, a process referred to as epileptogenesis. This period plays a critical role in halting the progression toward epilepsy before the onset of abnormal molecular and network alterations. In this study, the fundamental concepts of epileptogenesis as well as the associated molecular and cellular targets are reviewed.

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Section: Disinhibitionmentioning

confidence: 99%

Understanding epileptogenesis from molecules to network alteration

Park

2024

encephalitis

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“…3 The addition of these signaling molecules and factors to tissue cultures of PSCs produces human MGE-like GABAergic progenitors. [4][5][6][7][8] This advance enabled further study of human GABAergic interneuron transplantation in rodent models of TLE, such as the intrahippocampal kainic acid model or the systemic pilocarpine model, that replicate neuropathological hallmarks of human TLE.…”

Section: Commentarymentioning

confidence: 99%

“…Zhu and colleagues have now addressed these important questions through an approach that generates highly enriched and differentiated human GABAergic neural progenitors from PSCs. 5 , 6 After transplantation, they conducted video-electroencephalography (v-EEG), comparing short versus long-term survival periods, to ask whether the transplants were effective in suppressing seizures over the long run. Remarkably, the transplanted cells maintained efficacy for suppressing seizures even up to 9 months.…”

Section: Commentarymentioning

confidence: 99%

Masterminding Hippocampal Circuits by Transplanting Human GABAergic Interneurons to Treat Temporal Lobe Epilepsy

Gupta

Naegele

2023

Epilepsy Curr

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“…This migratory capacity, together with their ability to integrate into host circuitry, has garnered interest to use them as a cell therapy for conditions like epilepsy (clinical trial: NCT05135091). Enthusiasm has been further engendered by the successful derivation of MCIPs from human stem cells and induced Pluripotent Stem Cells (iPSCs) and their use in preclinical therapeutic transplantation studies 15,16 .…”

Section: Introductionmentioning

confidence: 99%

Interneurons that BiTE: Harnessing the migratory capacity of cortical inhibitory interneuron precursors to treat high-grade glioma

Brosius,

Manley,

Harvey

et al. 2024

Preprint

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Glioblastoma has a poor prognosis with limited therapeutic options. To date, almost all therapeutic agents that showed promise in in vitro assays, preclinical trials, or even in early clinical trials have failed to make a substantial impact on the survival of patients with high-grade glioma. One major obstacle for small molecules, therapeutic proteins or immune cells, remains the blood brain barrier, which often prevents the efficient delivery of agents to the tumor. To address this delivery issue, we developed a cellular vector, where implanted modified post-mitotic Migratory Cortical Inhibitory Interneuron Precursors (MCIPs) migrate to high-grade glioma by chemoattraction to locally secrete a therapeutic protein. The inhibitory interneurons of the cerebral cortex originate predominantly in the ventral/subcortical portion of the telencephalic neural tube. During fetal brain development, MCIP migration is guided over long distances by chemorepulsant and chemoattractant factors. Remarkably, several of the MCIP chemoattractant factors are also secreted by high-grade gliomas. Indeed, our in vitro and in vivo data show that MCIPs robustly migrate to the majority of glioblastoma evaluated. As a proof of principle, we modified the MCIPs to secrete bispecific T-cell engagers (BiTEs), in essence two linked antibodies that connect 2 antigens of choice. We chose to link the EGFR tumor antigen to CD3 (T-cell receptor) on T-cells to create an adaptor molecule that induces an anti-tumor response of resident and supplied T-cells by bridging a tumor antigen and the T-cell receptor. We find that implanted BITE-secreting MCIPs significantly extended survival of mice injected with high-grade glioma. Therefore, we conclude that the use of MCIPs as a delivery vector for therapeutic agents could revolutionize the way we treat glioblastoma, as they allow for the local delivery of therapeutic agents in high concentrations, bypassing the need for these agents to cross the blood brain barrier while reducing the risk for systemic toxicities outside of the brain.

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Human cortical interneurons optimized for grafting specifically integrate, abort seizures, and display prolonged efficacy without over-inhibition

Cited by 11 publications

References 76 publications

Understanding epileptogenesis from molecules to network alteration

Understanding epileptogenesis from molecules to network alteration

Masterminding Hippocampal Circuits by Transplanting Human GABAergic Interneurons to Treat Temporal Lobe Epilepsy

Interneurons that BiTE: Harnessing the migratory capacity of cortical inhibitory interneuron precursors to treat high-grade glioma

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