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Gene therapy in epilepsy: neuropeptides and neurotrophic factors

Kanter Schlifke, Irene LU (2007) In Lund University Faculty of Medicine Doctoral Dissertation Series 2007:155.
Abstract
Temporal lobe epilepsy (TLE) is the most common form of epilepsy among adult patients, and the most problematic one as seizures cannot be controlled by currently available drugs in 30 % of patients. Gene therapy based on overexpression of endogenous anti-epileptic agents such as the neuropeptide galanin and the glial cell line-derived neurotrophic factor (GDNF) represents a promising new approach for treatment of TLE. Using this strategy, supply of the respective therapeutic agent is restricted to the brain structure where seizure suppression is both necessary and sufficient, without disturbing normal function in other brain areas.



In the present thesis, the anti-epileptic potential of local gene therapy-based increase... (More)
Temporal lobe epilepsy (TLE) is the most common form of epilepsy among adult patients, and the most problematic one as seizures cannot be controlled by currently available drugs in 30 % of patients. Gene therapy based on overexpression of endogenous anti-epileptic agents such as the neuropeptide galanin and the glial cell line-derived neurotrophic factor (GDNF) represents a promising new approach for treatment of TLE. Using this strategy, supply of the respective therapeutic agent is restricted to the brain structure where seizure suppression is both necessary and sufficient, without disturbing normal function in other brain areas.



In the present thesis, the anti-epileptic potential of local gene therapy-based increase of galanin and GDNF was determined in different animal models for TLE, i.e., kindling and status epilepticus. Target areas for localised overexpression were the hippocampus, a common structure of seizure origin, and the piriform cortex (PC), an area important in seizure generalisation. Galanin was overexpressed either in transgenic mice (paper I), or in rats using a viral vector (paper II). GDNF gene therapy was based on in vivo transduction of endogenous cells by viral vector (papers III and IV) or on transplantation of in vitro-manipulated, encapsulated cells (paper V).



The data collected in this thesis show that increased supply of galanin and GDNF in the PC and/or the hippocampus influenced in particular generalised seizure activity in different models for TLE. These findings demonstrate that gene therapy based on overexpression of galanin and GDNF represents a promising approach for control of epileptic seizures. However, in order to also achieve modulation of initial seizure threshold and overall epileptogenesis, the pathways of galanin and GDNF anti-epileptic effects have to be understood in more detail and gene transfer methods have to be modified accordingly to reach optimal temporal and spatial overexpression and release. (Less)
Abstract (Swedish)
Popular Abstract in Swedish

Normal hjärnaktivitet är beroende på en delikat balans mellan inhibitorisk och excitatorisk nervcellssignallering. Om denna balans störs och lutar mer åt en ökad excitering uppstår epileptiska anfall. Ungefär 1 % av befolkningen i västvärldens drabbas av epilepsi, framförallt av temporallobs-epilepsi (TLE) vilket är den vanligast förekommande formen av epilepsi bland vuxna patienter. De mediciner som finns på marknaden idag kan bara erbjuda kontroll av de epileptiska anfallen åt 70% av TLE-patienterna, och orsakar dessutom ofta besvärande biverkningar. Det finns alltså ett stort behov att utveckla mer effektiva och bättre tolererade behandlingar. Genterapi baserat på överuttryck av endogena... (More)
Popular Abstract in Swedish

Normal hjärnaktivitet är beroende på en delikat balans mellan inhibitorisk och excitatorisk nervcellssignallering. Om denna balans störs och lutar mer åt en ökad excitering uppstår epileptiska anfall. Ungefär 1 % av befolkningen i västvärldens drabbas av epilepsi, framförallt av temporallobs-epilepsi (TLE) vilket är den vanligast förekommande formen av epilepsi bland vuxna patienter. De mediciner som finns på marknaden idag kan bara erbjuda kontroll av de epileptiska anfallen åt 70% av TLE-patienterna, och orsakar dessutom ofta besvärande biverkningar. Det finns alltså ett stort behov att utveckla mer effektiva och bättre tolererade behandlingar. Genterapi baserat på överuttryck av endogena anti-epileptiska substanser, som t.ex. neuropeptiden galanin och den neurotrofa faktorn GDNF erbjuder en lovande infallsvinkel för behandling av TLE. Fördelen med denna strategi är att tillskottet av respektive terapeutisk agent begränsas till det område där anfallsundertryck behövs och påverkar därför inte funktionen i övriga delar av hjärnan.



I denna avhandling har den anti-epileptiska potentialen av en lokal genterapeutisk ökning av galanin och GDNF i två olika djurmodeller av TLE, kindling och status epilepticus, undersökts. Målområdet för överuttrycket av generna var hippocampus, en struktur där epileptiska anfall vanligvis initieras, och piriforma cortex (PC), ett område som spelar en stor roll i generaliseringen av epileptiska anfall. Galanin överuttrycktes i antingen transgena möss (artikel I), eller med hjälp av en virusvektor i råttor (artikel II). Genterapi med GDNF baserades på en in vivo transduktion av endogena celler med hjälp av virusvektorer (artikel III och IV), eller via transplantation av in vitro-manipulerade inkapslade celler (artikel V).



Resultaten visar att ett ökat tillskott av galanin och GDNF i PC och/eller hippocampus, påverkar framförallt den generaliserade anfallsaktiviteten i olika modeller av TLE. Dessa fynd visar att ett genterapeutiskt överuttryck av galanin och GDNF är en lovande strategi för att kontrollera epileptiska anfall. För att också uppnå en förhöjning av anfallströskeln och för att kunna påverka epileptogenesen i allmänhet, krävs dock vidare undersökningar. Om det vägar GDNF och galanin användar sig av för att uppnå sin anti-epileptiska verkan kan förstås i större detalj, skulle förbättringar av metoden kunna ske, t.ex. vad gäller optimal överuttrycksnivå av respektive substans, och även var och när detta överuttryck ska ske. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Prof. Sperk, Guenther, Department of Pharmacology, Innsbruck Medical University, Innsbruck, Austria
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Neurologi, neurophysiology, neuropsychology, Neurology, piriform cortex, hippocampus, neuropsykologi, encapsulated cells, viral vectors, GDNF, galanin, epilepsy, gene therapy, neurofysiologi
in
Lund University Faculty of Medicine Doctoral Dissertation Series
volume
2007:155
pages
141 pages
publisher
Section of Restorative Neurology, Division of Neurology, Department of Clinical Sciences, Lund University, Lund, Sweden
defense location
Segerfalksalen, BMC A-10, Sölvegatan 17, 22184 Lund
defense date
2007-11-23 09:15:00
ISSN
1652-8220
ISBN
978-91-85897-33-9
language
English
LU publication?
yes
additional info
I Schlifke, E Kuteeva, T Hökfelt and M Kokaia. 2006. Galanin expressed in the excitatory fibers attenuates synaptic strength and generalized seizures in the piriform cortex of mice. Experimental Neurology, vol 200 pp 398-406.
I Kanter-Schlifke, A.T. Sørensen, M Ledri, E Kuteeva, T Hökfelt and M Kokaia. . Galanin gene transfer curtails generalized seizures in kindled rats without altering hippocampal synaptic plasticity. Neuroscience, (inpress)
I Kanter-Schlifke, B Georgievska, D Kirik and M Kokaia. 2007. Brain area, age and viral vector-specific glial cell line-derived neurotrophic factor expression and transport in rat. Neuroreport, vol 11;18 pp 845-50.
I Kanter-Schlifke, B Georgievska, D Kirik and M Kokaia. 2007. Seizure Suppression by GDNF Gene Therapy in Animal Models of Epilepsy. Mol Ther, vol 15 pp 1106-13.
I Kanter-Schlifke, L Fjord-Larsen, P Kusk, M Ängehagen, L Wahlberg and M Kokaia. . GDNF released from encapsulated cells suppresses seizure activity in the epileptic hippocampus. (manuscript)
The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Restorative Neurology (0131000160)
id
4dbacc89-fd2d-4b3b-93e7-dacd40b28a3e (old id 599189)
date added to LUP
2016-04-01 16:21:38
date last changed
2019-05-22 06:10:28
@phdthesis{4dbacc89-fd2d-4b3b-93e7-dacd40b28a3e,
  abstract     = {{Temporal lobe epilepsy (TLE) is the most common form of epilepsy among adult patients, and the most problematic one as seizures cannot be controlled by currently available drugs in 30 % of patients. Gene therapy based on overexpression of endogenous anti-epileptic agents such as the neuropeptide galanin and the glial cell line-derived neurotrophic factor (GDNF) represents a promising new approach for treatment of TLE. Using this strategy, supply of the respective therapeutic agent is restricted to the brain structure where seizure suppression is both necessary and sufficient, without disturbing normal function in other brain areas.<br/><br>
<br/><br>
In the present thesis, the anti-epileptic potential of local gene therapy-based increase of galanin and GDNF was determined in different animal models for TLE, i.e., kindling and status epilepticus. Target areas for localised overexpression were the hippocampus, a common structure of seizure origin, and the piriform cortex (PC), an area important in seizure generalisation. Galanin was overexpressed either in transgenic mice (paper I), or in rats using a viral vector (paper II). GDNF gene therapy was based on in vivo transduction of endogenous cells by viral vector (papers III and IV) or on transplantation of in vitro-manipulated, encapsulated cells (paper V).<br/><br>
<br/><br>
The data collected in this thesis show that increased supply of galanin and GDNF in the PC and/or the hippocampus influenced in particular generalised seizure activity in different models for TLE. These findings demonstrate that gene therapy based on overexpression of galanin and GDNF represents a promising approach for control of epileptic seizures. However, in order to also achieve modulation of initial seizure threshold and overall epileptogenesis, the pathways of galanin and GDNF anti-epileptic effects have to be understood in more detail and gene transfer methods have to be modified accordingly to reach optimal temporal and spatial overexpression and release.}},
  author       = {{Kanter Schlifke, Irene}},
  isbn         = {{978-91-85897-33-9}},
  issn         = {{1652-8220}},
  keywords     = {{Neurologi; neurophysiology; neuropsychology; Neurology; piriform cortex; hippocampus; neuropsykologi; encapsulated cells; viral vectors; GDNF; galanin; epilepsy; gene therapy; neurofysiologi}},
  language     = {{eng}},
  publisher    = {{Section of Restorative Neurology, Division of Neurology, Department of Clinical Sciences, Lund University, Lund, Sweden}},
  school       = {{Lund University}},
  series       = {{Lund University Faculty of Medicine Doctoral Dissertation Series}},
  title        = {{Gene therapy in epilepsy: neuropeptides and neurotrophic factors}},
  volume       = {{2007:155}},
  year         = {{2007}},
}