Gene therapy in epilepsy: neuropeptides and neurotrophic factors

Research output: ThesisDoctoral Thesis (compilation)

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 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.

Details

Authors
  • Irene Kanter Schlifke
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Neurosciences

Keywords

  • Neurologi, neurophysiology, neuropsychology, Neurology, piriform cortex, hippocampus, neuropsykologi, encapsulated cells, viral vectors, GDNF, galanin, epilepsy, gene therapy, neurofysiologi
Original languageEnglish
QualificationDoctor
Awarding Institution
Supervisors/Assistant supervisor
Award date2007 Nov 23
Publisher
  • Section of Restorative Neurology, Division of Neurology, Department of Clinical Sciences, Lund University, Lund, Sweden
Print ISBNs978-91-85897-33-9
Publication statusPublished - 2007
Publication categoryResearch

Bibliographic note

Defence details Date: 2007-11-23 Time: 09:15 Place: Segerfalksalen, BMC A-10, Sölvegatan 17, 22184 Lund External reviewer(s) Name: Sperk, Guenther Title: Prof. Affiliation: Department of Pharmacology, Innsbruck Medical University, Innsbruck, Austria --- The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Restorative Neurology (0131000160)