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Cell and Gene Therapy for Parkinson's Disease: Therapeutic Effect and Modulation of Dyskinesias in the 6-OHDA Rat Model

Carlsson, Thomas LU (2007)
Abstract (Swedish)
Popular Abstract in Swedish

Parkinsons sjukdom uppstår när celler som producerar signalsubstansen dopamin i hjärnan dör. Detta leder till att de drabbade patienterna blir stela, får långsamma rörelser, svårt att påbörja och avsluta rörelser och även skakningar i framförallt armar och händer. Idag finns inget sätt att bota sjukdomen. Dock finns det läkemedel som kan lindra symptomen. Den vanligaste medicinen är L-DOPA, vilket är en molekyl som kan omvandlas till dopamin i hjärnan. Denna behandling fungerar bra under de första 5-10 åren efter det att sjukdomen diagnostiserats. Dock, tyvärr, ju längre sjukdomen pågår, desto mindre effekt har L-DOPA medicineringen och många patienter utvecklar biverkningar som yttrar sig som... (More)
Popular Abstract in Swedish

Parkinsons sjukdom uppstår när celler som producerar signalsubstansen dopamin i hjärnan dör. Detta leder till att de drabbade patienterna blir stela, får långsamma rörelser, svårt att påbörja och avsluta rörelser och även skakningar i framförallt armar och händer. Idag finns inget sätt att bota sjukdomen. Dock finns det läkemedel som kan lindra symptomen. Den vanligaste medicinen är L-DOPA, vilket är en molekyl som kan omvandlas till dopamin i hjärnan. Denna behandling fungerar bra under de första 5-10 åren efter det att sjukdomen diagnostiserats. Dock, tyvärr, ju längre sjukdomen pågår, desto mindre effekt har L-DOPA medicineringen och många patienter utvecklar biverkningar som yttrar sig som okontrollerade och onormala rörelser, så kallade dyskinesier. En behandlingsmetod som har utvärderats för att bota och/eller lindra symptomen är transplantationer av dopaminceller från fostervävnad. Dessa studier har visat goda resultat hos vissa patienter men effekten av transplantaten har varit mycket varierande, och några patienter har utvecklat bevärande dyskinesier.



I min avhandling har jag framförallt fokuserat mig på att undersöka uppkomsten av de ofrivilliga rörelserna, dyskinesierna, och effekten av celltransplantationer på dessa dyskinesier in en råttmodell av Parkinsons sjukdom. Målet är att klarlägga vilka faktorer som påverkar utvecklingen av dyskinesier och vad som leder till de stora skillnader man sett mellan olika patienter. Vidare har jag studerat en ny genterapiteknik som bygger på att överuttrycka de gener som styr dopaminproduktionen i hjärnan, och utvärderat denna behandlingsmetods inverkan på dyskinesierna.



Resultaten visar att transplantationer av fostercellsvävnad troligen ger bäst resultat när patienterna inte har en alltför långt framskriden sjukdom. Vidare är placeringen av cellerna i hjärnan och vilka typer av celler som transplanteras mycket viktiga för hur bra de kan motverka bieffekterna som uppkommer från L-DOPA-behandlingen. Vi visar också att celler som producerar signalsubstansen serotonin är en viktig faktor för uppkomsten av dyskinesier. Detta innefattar både hjärnans egna serotoninsystem men också de serotoninceller som finns i den transplanterade vävnaden. Slutligen, genterapi för lokal kontinuerlig produktion av L-DOPA direkt i hjärnan visar mycket lovande resultat, både en markant förbättring av den motoriska funktionen och en effektiv blockering av de L-DOPA-inducerade dyskinesierna. (Less)
Abstract
The main pathological feature in Parkinson's disease is the progressive loss of dopamine neurons in the midbrain, which in turn leads to the appearance of motor deficits such as akinesia/bradykinesia (loss/slowness of movements), rigidity, postural imbalance and tremor. To this day, there is no cure for the disease, but there are medications to relieve the symptoms. The gold standard medication is the administration of the precursor of dopamine, L-DOPA, which is very efficient within the first years. Unfortunately, for the majority of the patients, this medication later leads to the development of abnormal involuntary movements, termed dyskinesias. These L-DOPA-induced dyskinesias are suggested to develop due to the route of the oral... (More)
The main pathological feature in Parkinson's disease is the progressive loss of dopamine neurons in the midbrain, which in turn leads to the appearance of motor deficits such as akinesia/bradykinesia (loss/slowness of movements), rigidity, postural imbalance and tremor. To this day, there is no cure for the disease, but there are medications to relieve the symptoms. The gold standard medication is the administration of the precursor of dopamine, L-DOPA, which is very efficient within the first years. Unfortunately, for the majority of the patients, this medication later leads to the development of abnormal involuntary movements, termed dyskinesias. These L-DOPA-induced dyskinesias are suggested to develop due to the route of the oral administration of the medication, which gives rise to intermittent and high fluctuations in the brain dopamine levels. Support for this has come from studies showing that continuous delivery of L-DOPA decreases the severity and magnitude of these side effects. In order to restore lost dopamine circuitry, fetal cell transplantation has been investigated as a potential treatment. The outcome of clinical trials has been highly variable, where some patients have shown very good response, while others displayed only marginal improvements to even a worsening of the L-DOPA-induced side effects. In addition, some patients have also experienced a new type of graft-induced dyskinesias in absence of any L-DOPA medication.



In this thesis work, I have investigated the role of the progressive neurodegeneration on the functional improvement, as well as the development and maintenance of L-DOPA- and graft-induced dyskinesias, after fetal cell transplantation in the 6-hydroxydopamine rat model of Parkinson's disease. Dyskinesias, in particular, have been studied in regard to graft placement and the role of the serotonin neurons in the graft as well as the role of the host serotonin system. In addition, I have investigated if continuous delivery of DOPA (endogenous L-DOPA) by viral vector-mediated gene transfer, of the dopamine-dependent enzymes tyrosine hydroxylase and GTP cyclohydrolase 1, can reverse L-DOPA-induced dyskinesias. The results demonstrate that progression of the DA lesion outside striatal areas can be detrimental for the functional impact of the fetal cell transplantation. Moreover, the location of the transplanted neurons in the striatum, and the presence of serotonin neurons in the grafted tissue may have an impact on development and maintenance of L-DOPA-induced dyskinesias. Finally, viral vector gene delivery strategy to replace DOPA in the striatum can effectively improve behavior function and reduce L-DOPA-induced dyskinesia in the rat model of Parkinson's disease. This novel gene therapy treatment hold great promise for future clinical applications. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Associate Professor Kang, Un, Department of Neurology, The University of Chicago, Chicago, Illinois, USA
organization
publishing date
type
Thesis
publication status
published
subject
keywords
neuropsykologi, Pharmacological sciences, pharmacognosy, pharmacy, neurofysiologi, Medicin (människa och djur), Neurology, neuropsychology, neurophysiology, Neurologi, Medicine (human and vertebrates), Parkinson?s disease, Serotonin, Tyrosine hydroxylase, Ventral mesenchephalon, Motor behavior, L-DOPA, GTP cyclohydrolase 1, Gene therapy, Dyskinesias, Cell transplantation, Dopamine, toxicology, Farmakologi, farmakognosi, farmaci, toxikologi
pages
164 pages
publisher
Thomas Carlsson
defense location
Segerfalksalen, Wallenberg Neuroscience Center, Lund, Sweden
defense date
2007-06-14 09:15
ISSN
1652-8220
ISBN
978-91-85559-90-9
language
English
LU publication?
yes
id
d7b8b127-ec6e-42e7-88c3-463bad706c93 (old id 548733)
date added to LUP
2007-09-10 14:37:28
date last changed
2016-09-19 08:44:57
@phdthesis{d7b8b127-ec6e-42e7-88c3-463bad706c93,
  abstract     = {The main pathological feature in Parkinson's disease is the progressive loss of dopamine neurons in the midbrain, which in turn leads to the appearance of motor deficits such as akinesia/bradykinesia (loss/slowness of movements), rigidity, postural imbalance and tremor. To this day, there is no cure for the disease, but there are medications to relieve the symptoms. The gold standard medication is the administration of the precursor of dopamine, L-DOPA, which is very efficient within the first years. Unfortunately, for the majority of the patients, this medication later leads to the development of abnormal involuntary movements, termed dyskinesias. These L-DOPA-induced dyskinesias are suggested to develop due to the route of the oral administration of the medication, which gives rise to intermittent and high fluctuations in the brain dopamine levels. Support for this has come from studies showing that continuous delivery of L-DOPA decreases the severity and magnitude of these side effects. In order to restore lost dopamine circuitry, fetal cell transplantation has been investigated as a potential treatment. The outcome of clinical trials has been highly variable, where some patients have shown very good response, while others displayed only marginal improvements to even a worsening of the L-DOPA-induced side effects. In addition, some patients have also experienced a new type of graft-induced dyskinesias in absence of any L-DOPA medication.<br/><br>
<br/><br>
In this thesis work, I have investigated the role of the progressive neurodegeneration on the functional improvement, as well as the development and maintenance of L-DOPA- and graft-induced dyskinesias, after fetal cell transplantation in the 6-hydroxydopamine rat model of Parkinson's disease. Dyskinesias, in particular, have been studied in regard to graft placement and the role of the serotonin neurons in the graft as well as the role of the host serotonin system. In addition, I have investigated if continuous delivery of DOPA (endogenous L-DOPA) by viral vector-mediated gene transfer, of the dopamine-dependent enzymes tyrosine hydroxylase and GTP cyclohydrolase 1, can reverse L-DOPA-induced dyskinesias. The results demonstrate that progression of the DA lesion outside striatal areas can be detrimental for the functional impact of the fetal cell transplantation. Moreover, the location of the transplanted neurons in the striatum, and the presence of serotonin neurons in the grafted tissue may have an impact on development and maintenance of L-DOPA-induced dyskinesias. Finally, viral vector gene delivery strategy to replace DOPA in the striatum can effectively improve behavior function and reduce L-DOPA-induced dyskinesia in the rat model of Parkinson's disease. This novel gene therapy treatment hold great promise for future clinical applications.},
  author       = {Carlsson, Thomas},
  isbn         = {978-91-85559-90-9},
  issn         = {1652-8220},
  keyword      = {neuropsykologi,Pharmacological sciences,pharmacognosy,pharmacy,neurofysiologi,Medicin (människa och djur),Neurology,neuropsychology,neurophysiology,Neurologi,Medicine (human and vertebrates),Parkinson?s disease,Serotonin,Tyrosine hydroxylase,Ventral mesenchephalon,Motor behavior,L-DOPA,GTP cyclohydrolase 1,Gene therapy,Dyskinesias,Cell transplantation,Dopamine,toxicology,Farmakologi,farmakognosi,farmaci,toxikologi},
  language     = {eng},
  pages        = {164},
  publisher    = {Thomas Carlsson},
  school       = {Lund University},
  title        = {Cell and Gene Therapy for Parkinson's Disease: Therapeutic Effect and Modulation of Dyskinesias in the 6-OHDA Rat Model},
  year         = {2007},
}