Enhancing neuronal inhibition by cell and gene therapy as a novel treatment for Epilepsy
(2022) In Lund University, Faculty of Medicine Doctoral Dissertation Series- Abstract
- Epilepsy is a family of heterogeneous and multifactorial neurological disorders, unified by the occurrence of spontaneous recurrent seizures. Overall, it affects 50 million people worldwide of all ages and genders. Available treatments are only symptomatic and have severe side effects, while they also fail to provide adequate seizure control in a third of the patients. Therefore, a cure is yet to be found. In this warrant for novel strategies to treat those refractory patients, this thesis evolved. The two approaches presented here based their goal on increasing inhibitory drive in the epileptic focus to reduce the pathological hyperexcitable neuronal network that characterizes epilepsy, and thus counteract seizures.
First, based on... (More) - Epilepsy is a family of heterogeneous and multifactorial neurological disorders, unified by the occurrence of spontaneous recurrent seizures. Overall, it affects 50 million people worldwide of all ages and genders. Available treatments are only symptomatic and have severe side effects, while they also fail to provide adequate seizure control in a third of the patients. Therefore, a cure is yet to be found. In this warrant for novel strategies to treat those refractory patients, this thesis evolved. The two approaches presented here based their goal on increasing inhibitory drive in the epileptic focus to reduce the pathological hyperexcitable neuronal network that characterizes epilepsy, and thus counteract seizures.
First, based on evidence of loss and/or alteration of gamma-aminobutyric acid (GABA)-ergic interneurons in the epileptic neuronal network, cell-based therapy has been developed and tested in three different scenarios for restoration of the excitatory/inhibitory balance. GABAergic interneurons (hdINs) were generated in vitro from human embryonic stem cells and proved to survive and integrate into both human and rodent epileptic environments. Host neuronal activity could be modulated by light-activation of hdINs using optogenetics. Finally, grafted hdINs were able to reduce the seizure frequency and total time spent in seizures in a rat model of temporal lobe epilepsy (TLE), the most common form of refractory epilepsy in adults. However, grafted hdINs failed to improve the pathology in a genetic mouse model of cortical dysplasia-focal epilepsy syndrome associated with autism spectrum disorder, which highlights the diversity of epilepsies and the need for gaining a better understanding of the mechanisms underpinning the disease.
Finally, direct inhibition of principal cells, similar to the one exerted by endogenous inhibitory interneurons, in the chronic epileptic hippocampus by using a chemogenetic approach delivered as gene therapy was also tested. Positive results were observed by decreasing ability to generate action potentials, although further investigation is required to evaluate the efficacy of this approach on seizures.
Collectively, the work presented here has moved the field forward in testing two different therapeutic strategies in a TLE model, and also one of them in a genetic epilepsy model. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/3097d63a-d99d-452a-8457-ed9191ba2b0b
- author
- Gonzalez Ramos, Ana LU
- supervisor
-
- Merab Kokaia LU
- My Andersson LU
- Marco Ledri LU
- opponent
-
- professor Parent, Jack, Michigan
- organization
- publishing date
- 2022
- type
- Thesis
- publication status
- published
- subject
- keywords
- Epilepsy, Interneurons, GABA, Human pluripotent stem cells, Cell therapy, Gene therapy, Chemogenetics, Hippocampus, TLE, Cntnap2
- in
- Lund University, Faculty of Medicine Doctoral Dissertation Series
- issue
- 2022:44
- pages
- 153 pages
- publisher
- Lund University, Faculty of Medicine
- defense location
- Segerfalksalen, BMC A10, Sölvegatan 17 i Lund. Join by Zoom: https://lu-se.zoom.us/j/64626471915
- defense date
- 2022-04-08 13:15:00
- ISSN
- 1652-8220
- ISBN
- 978-91-8021-205-2
- language
- English
- LU publication?
- yes
- id
- 3097d63a-d99d-452a-8457-ed9191ba2b0b
- date added to LUP
- 2022-03-08 14:40:16
- date last changed
- 2022-03-29 11:21:38
@phdthesis{3097d63a-d99d-452a-8457-ed9191ba2b0b,
abstract = {{Epilepsy is a family of heterogeneous and multifactorial neurological disorders, unified by the occurrence of spontaneous recurrent seizures. Overall, it affects 50 million people worldwide of all ages and genders. Available treatments are only symptomatic and have severe side effects, while they also fail to provide adequate seizure control in a third of the patients. Therefore, a cure is yet to be found. In this warrant for novel strategies to treat those refractory patients, this thesis evolved. The two approaches presented here based their goal on increasing inhibitory drive in the epileptic focus to reduce the pathological hyperexcitable neuronal network that characterizes epilepsy, and thus counteract seizures.<br/>First, based on evidence of loss and/or alteration of gamma-aminobutyric acid (GABA)-ergic interneurons in the epileptic neuronal network, cell-based therapy has been developed and tested in three different scenarios for restoration of the excitatory/inhibitory balance. GABAergic interneurons (hdINs) were generated in vitro from human embryonic stem cells and proved to survive and integrate into both human and rodent epileptic environments. Host neuronal activity could be modulated by light-activation of hdINs using optogenetics. Finally, grafted hdINs were able to reduce the seizure frequency and total time spent in seizures in a rat model of temporal lobe epilepsy (TLE), the most common form of refractory epilepsy in adults. However, grafted hdINs failed to improve the pathology in a genetic mouse model of cortical dysplasia-focal epilepsy syndrome associated with autism spectrum disorder, which highlights the diversity of epilepsies and the need for gaining a better understanding of the mechanisms underpinning the disease.<br/>Finally, direct inhibition of principal cells, similar to the one exerted by endogenous inhibitory interneurons, in the chronic epileptic hippocampus by using a chemogenetic approach delivered as gene therapy was also tested. Positive results were observed by decreasing ability to generate action potentials, although further investigation is required to evaluate the efficacy of this approach on seizures.<br/>Collectively, the work presented here has moved the field forward in testing two different therapeutic strategies in a TLE model, and also one of them in a genetic epilepsy model.}},
author = {{Gonzalez Ramos, Ana}},
isbn = {{978-91-8021-205-2}},
issn = {{1652-8220}},
keywords = {{Epilepsy; Interneurons; GABA; Human pluripotent stem cells; Cell therapy; Gene therapy; Chemogenetics; Hippocampus; TLE; Cntnap2}},
language = {{eng}},
number = {{2022:44}},
publisher = {{Lund University, Faculty of Medicine}},
school = {{Lund University}},
series = {{Lund University, Faculty of Medicine Doctoral Dissertation Series}},
title = {{Enhancing neuronal inhibition by cell and gene therapy as a novel treatment for Epilepsy}},
url = {{https://lup.lub.lu.se/search/files/115037596/Thesis_Ana_WEB.pdf}},
year = {{2022}},
}