Advancing gene therapy for epilepsy. Translational pre-clinical studies with neuropeptide Y and glial cell-line derived neurotrophic factor.

Research output: ThesisDoctoral Thesis (compilation)

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Advancing gene therapy for epilepsy. Translational pre-clinical studies with neuropeptide Y and glial cell-line derived neurotrophic factor. / Melin, Esbjörn.

Lund : Lund University, Faculty of Medicine, 2020. 100 p.

Research output: ThesisDoctoral Thesis (compilation)

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Melin E. Advancing gene therapy for epilepsy. Translational pre-clinical studies with neuropeptide Y and glial cell-line derived neurotrophic factor.. Lund: Lund University, Faculty of Medicine, 2020. 100 p. (Lund University, Faculty of Medicine Doctoral Dissertation Series; 2020:24).

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RIS

TY - THES

T1 - Advancing gene therapy for epilepsy. Translational pre-clinical studies with neuropeptide Y and glial cell-line derived neurotrophic factor.

AU - Melin, Esbjörn

N1 - Defence details Date: 2020-03-27 Time: 13:15 Place: Segerfalksalen, BMC A10, Sölvegatan 17 i Lund External reviewer(s) Name: Henshall, David Title: PhD Affiliation: Royal College of Surgeons in Ireland

PY - 2020

Y1 - 2020

N2 - Epilepsy is a neurological disorder, affecting approximately 1% of the population. The high rate of drug-resistance in epilepsy in general (30%), and temporal lobe epilepsy (TLE) in particular, pose a serious clinical problem. Thus, novel treatments for drug-resistant epilepsy is highly warranted. Gene therapy has been suggested to be a promising approach to target drug-resistant focal epilepsy since it offers the opportunity of delivering therapeutic agents directly into the seizure focus, thereby possibly being more effective in suppressing seizures and causing less adverse effects than conventional anti-seizure drugs. Two endogenous proteins that have been shown to be able to modulate seizures when delivered by gene therapy are neuropeptide Y (NPY) through its interaction with the Y2 receptor and glial cell-line derived neurotrophic factor (GDNF). In this thesis, the seizure supressing potential of these two theraputic strategies was investigated in an animal model of TLE. In the case of combinatorial NPY and Y2 receptor, overexpression was achived via adeno-associated viral (AAV) vector mediated in-vivo gene therapy. GDNF levels were increased by ex-vivo gene therapy via encapsulated cell biodelivery (ECB). The efficacy studies were performed in a manner that is suggested to increase the translational value of the results. Thus, both strategies were evaluated by continous video-EEG monitoring in the intrahippocampal kainic acid (KA) rat model of post status epilepticus spontanous recurrent seizures (SRSs), which is considered to share pathopysiology with human TLE. Moreover, the treatments were individualized by MRI to target the hippocampal seizure focus, ipsilateral to the injection of KA.The results indicate that both combinatorial NPY and Y2 receptor overexpression and ECB of GDNF were capable of reducing the frequency of SRSs when administered unilaterally in the seizure focus, with a responder rate of 31.3% respective 50%. Moreover, AAV derived overexpression of the NPY and Y2 receptor moduated SRS clustering patterns by increasing the latency between individual SRSs, but also between SRS clusters. These findings further strengthes the translational potential for these gene therapy strategies of treating TLE.Finally, the insights from the work with the model contributed to an attemt at harmonizing experimental procedures and standardising data collection within the field of pre-clinical epilepsy research. The implementation of common data elements (CDEs) might serve as support for future multicenter studies, which would improve reproducibility and hopefully enhance translation of preclinical findings to the clinic.

AB - Epilepsy is a neurological disorder, affecting approximately 1% of the population. The high rate of drug-resistance in epilepsy in general (30%), and temporal lobe epilepsy (TLE) in particular, pose a serious clinical problem. Thus, novel treatments for drug-resistant epilepsy is highly warranted. Gene therapy has been suggested to be a promising approach to target drug-resistant focal epilepsy since it offers the opportunity of delivering therapeutic agents directly into the seizure focus, thereby possibly being more effective in suppressing seizures and causing less adverse effects than conventional anti-seizure drugs. Two endogenous proteins that have been shown to be able to modulate seizures when delivered by gene therapy are neuropeptide Y (NPY) through its interaction with the Y2 receptor and glial cell-line derived neurotrophic factor (GDNF). In this thesis, the seizure supressing potential of these two theraputic strategies was investigated in an animal model of TLE. In the case of combinatorial NPY and Y2 receptor, overexpression was achived via adeno-associated viral (AAV) vector mediated in-vivo gene therapy. GDNF levels were increased by ex-vivo gene therapy via encapsulated cell biodelivery (ECB). The efficacy studies were performed in a manner that is suggested to increase the translational value of the results. Thus, both strategies were evaluated by continous video-EEG monitoring in the intrahippocampal kainic acid (KA) rat model of post status epilepticus spontanous recurrent seizures (SRSs), which is considered to share pathopysiology with human TLE. Moreover, the treatments were individualized by MRI to target the hippocampal seizure focus, ipsilateral to the injection of KA.The results indicate that both combinatorial NPY and Y2 receptor overexpression and ECB of GDNF were capable of reducing the frequency of SRSs when administered unilaterally in the seizure focus, with a responder rate of 31.3% respective 50%. Moreover, AAV derived overexpression of the NPY and Y2 receptor moduated SRS clustering patterns by increasing the latency between individual SRSs, but also between SRS clusters. These findings further strengthes the translational potential for these gene therapy strategies of treating TLE.Finally, the insights from the work with the model contributed to an attemt at harmonizing experimental procedures and standardising data collection within the field of pre-clinical epilepsy research. The implementation of common data elements (CDEs) might serve as support for future multicenter studies, which would improve reproducibility and hopefully enhance translation of preclinical findings to the clinic.

KW - Epilepsy

KW - Gene Therapy

KW - neuropeptide Y ( NPY)

KW - Y2 receptor

KW - GDNF

KW - Encapsulated cell biodelivery

KW - seizure

KW - In-vivo

M3 - Doctoral Thesis (compilation)

SN - 978-91-7619-884-1

T3 - Lund University, Faculty of Medicine Doctoral Dissertation Series

PB - Lund University, Faculty of Medicine

CY - Lund

ER -