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Novel strategies for enzyme replacement with gene therapy in models of Parkinson’s disease

Cederfjäll, Erik LU (2014) In Lund University, Faculty of Medicine, Doctoral Dissertation Series 2014:47.
Abstract (Swedish)
Popular Abstract in Swedish

Ungefär 22 000 svenskar lever i dag med Parkinsons sjukdom som är en hjärnsjukdom

där särskilda nervceller som normalt producerar signalsubstansen dopamin dör av okänd

anledning. Dessa nervceller har en viktig funktion eftersom de möjliggör vår rörelseförmåga

och brist på dopamin leder till rörelsenedsättning där patienten uppvisar symptomen

långsamhet, skakningar, muskelstelhet samt hopsjunken hållning. Utöver de tragiska sociala

följderna för den drabbade och dennes omgivning medför sjukdomen stora samhällsekonomiska

konsekvenser – såväl direkta kostnader för sjukvård och läkemedel, som indirekta i form av arbetsbortfall. I dag finns endast... (More)
Popular Abstract in Swedish

Ungefär 22 000 svenskar lever i dag med Parkinsons sjukdom som är en hjärnsjukdom

där särskilda nervceller som normalt producerar signalsubstansen dopamin dör av okänd

anledning. Dessa nervceller har en viktig funktion eftersom de möjliggör vår rörelseförmåga

och brist på dopamin leder till rörelsenedsättning där patienten uppvisar symptomen

långsamhet, skakningar, muskelstelhet samt hopsjunken hållning. Utöver de tragiska sociala

följderna för den drabbade och dennes omgivning medför sjukdomen stora samhällsekonomiska

konsekvenser – såväl direkta kostnader för sjukvård och läkemedel, som indirekta i form av arbetsbortfall. I dag finns endast läkemedel med lindrande effekt som fungerar genom att tillfälligt återställa dopaminnivåerna i hjärnan. Efter en tids behandling uppkommer dock biverkningar. Man tror att dessa beror på det fortskridande sjukdomsförloppet samt att läkemedlen har en bidragande orsak då man behandlar hela hjärnan och inte bara det mest utsatta området. När biverkningarna blir för svåra för den drabbade återstår få behandlingsalternativ och förhoppningarna ställs till nya forskningsframsteg.

Målet med genterapi är att återskapa eller reparera funktionen i områden som skadats av sjukdom. I undersökningarna som redovisas i denna avhandling används genterapi för att återskapa dopaminproduktionen i den Parkinson-sjuka hjärnan genom att få andra nervceller att ta över de döende dopaminproducerande nervcellernas uppgift. Detta åstadkommer vi genom att infoga den genetiska information som behövs för dopaminproduktion i den mest utsatta regionen i hjärnan. Forskningen som presenteras visar lovande resultat i försöksdjur med Parkinson-liknande symptom, där behandlingen återskapat dopaminproduktionen och djurens rörelseförmåga har återställts. Styrkan med behandlingen jämfört med dagens tillgängliga läkemedel är att den skapar en mer konstant och jämnare nivå av dopamin i hjärnan. Målet är att patienten ska slippa ta läkemedel flera gånger dagligen vilket ger en ojämn behandlingseffekt. Biverkningarna med nuvarande läkemedel tror vi kan undvikas med jämnare dopaminnivåer samt behandling av det mest påverkade området i hjärnan. Målsättningen är att forskningen ska leda till klinisk prövning och i framtiden förhoppningsvis till ett nytt behandlingsalternativ för patienter med Parkinsons sjukdom. (Less)
Abstract
Parkinson’s disease is a brain disorder characterized by loss of dopaminergic neurons in the midbrain, resulting in the characteristic motor symptoms: resting tremor, rigidity, akinesia and postural instability. Symptomatic treatment is based on reconstituting the loss of dopamine in the brain, primarily by oral administration of its precursor L-DOPA. Although this drug is effective in the early years of treatment, patients experience troublesome side effects over time that are believed to develop at least partly due to route of administration in addition to the progressive worsening of the disease. An alternative to oral L-DOPA administration is continuous DOPA synthesis with gene therapy. This can be achieved by expressing enzymes needed... (More)
Parkinson’s disease is a brain disorder characterized by loss of dopaminergic neurons in the midbrain, resulting in the characteristic motor symptoms: resting tremor, rigidity, akinesia and postural instability. Symptomatic treatment is based on reconstituting the loss of dopamine in the brain, primarily by oral administration of its precursor L-DOPA. Although this drug is effective in the early years of treatment, patients experience troublesome side effects over time that are believed to develop at least partly due to route of administration in addition to the progressive worsening of the disease. An alternative to oral L-DOPA administration is continuous DOPA synthesis with gene therapy. This can be achieved by expressing enzymes needed for DOPA synthesis in neurons in the striatum, where the loss of dopamine is most profound in Parkinson’s disease. The addition of two enzymes is necessary for efficient synthesis of DOPA in striatal neurons, namely tyrosine hydroxylase (TH) and GTP cyclohydrolase 1 (GCH1), and these can be delivered with an adeno-associated virus (AAV) vector. In the first two studies in this thesis, a new AAV vector design including TH and GCH1 was developed and validated in a rat model of Parkinson’s disease. Expression of this vector in parkinsonian rats resulted in complete recovery in different tests of motor function and was dose dependent. The therapeutic efficacy in this model was associated with increased levels of DOPA and dopamine in the striatum and histological analysis

showed widespread expression of both enzymes. The vector was also tested in a non-human

primate model of Parkinson’s disease that showed safety but not efficacy. The aim of the third study in this thesis was to implement a regulation mechanism for the continuous DOPA synthesis approach. This is a long-standing goal for gene therapy and the strategy used here was based on destabilizing domains (DD) and the ligand trimethoprim (TMP). Combining DD regulation with the continuous DOPA synthesis approach resulted robust efficacy in parkinsonian rats when given TMP. In addition, the basal expression in absence of the TMP ligand was minimal. Efficacy of this approach should now be validated in nonhuman primates before clinical translation can begin. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Professor Mazarakis, Nicholas, Department of Medicine, Imperial College London, London, UK
organization
publishing date
type
Thesis
publication status
published
subject
keywords
AAV vectors, dopamine, enzyme replacement, gene regulation, GTP cyclohydrolase 1, L-DOPA, tyrosine hydroxylase, Parkinson’s disease
in
Lund University, Faculty of Medicine, Doctoral Dissertation Series
volume
2014:47
pages
140 pages
publisher
Brain Repair and Imaging in Neural Systems (BRAINS)
defense location
Segerfalksalen, Wallenberg Neuroscience Center, Lund, Sweden
defense date
2014-04-25 09:00
ISSN
1652-8220
ISBN
978-91-87651-73-1
language
English
LU publication?
yes
id
b6b26b49-a8e1-4312-8048-750e980c9de0 (old id 4389535)
date added to LUP
2014-04-08 11:53:17
date last changed
2016-09-19 08:44:50
@phdthesis{b6b26b49-a8e1-4312-8048-750e980c9de0,
  abstract     = {Parkinson’s disease is a brain disorder characterized by loss of dopaminergic neurons in the midbrain, resulting in the characteristic motor symptoms: resting tremor, rigidity, akinesia and postural instability. Symptomatic treatment is based on reconstituting the loss of dopamine in the brain, primarily by oral administration of its precursor L-DOPA. Although this drug is effective in the early years of treatment, patients experience troublesome side effects over time that are believed to develop at least partly due to route of administration in addition to the progressive worsening of the disease. An alternative to oral L-DOPA administration is continuous DOPA synthesis with gene therapy. This can be achieved by expressing enzymes needed for DOPA synthesis in neurons in the striatum, where the loss of dopamine is most profound in Parkinson’s disease. The addition of two enzymes is necessary for efficient synthesis of DOPA in striatal neurons, namely tyrosine hydroxylase (TH) and GTP cyclohydrolase 1 (GCH1), and these can be delivered with an adeno-associated virus (AAV) vector. In the first two studies in this thesis, a new AAV vector design including TH and GCH1 was developed and validated in a rat model of Parkinson’s disease. Expression of this vector in parkinsonian rats resulted in complete recovery in different tests of motor function and was dose dependent. The therapeutic efficacy in this model was associated with increased levels of DOPA and dopamine in the striatum and histological analysis<br/><br>
showed widespread expression of both enzymes. The vector was also tested in a non-human<br/><br>
primate model of Parkinson’s disease that showed safety but not efficacy. The aim of the third study in this thesis was to implement a regulation mechanism for the continuous DOPA synthesis approach. This is a long-standing goal for gene therapy and the strategy used here was based on destabilizing domains (DD) and the ligand trimethoprim (TMP). Combining DD regulation with the continuous DOPA synthesis approach resulted robust efficacy in parkinsonian rats when given TMP. In addition, the basal expression in absence of the TMP ligand was minimal. Efficacy of this approach should now be validated in nonhuman primates before clinical translation can begin.},
  author       = {Cederfjäll, Erik},
  isbn         = {978-91-87651-73-1},
  issn         = {1652-8220},
  keyword      = {AAV vectors,dopamine,enzyme replacement,gene regulation,GTP cyclohydrolase 1,L-DOPA,tyrosine hydroxylase,Parkinson’s disease},
  language     = {eng},
  pages        = {140},
  publisher    = {Brain Repair and Imaging in Neural Systems (BRAINS)},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine, Doctoral Dissertation Series},
  title        = {Novel strategies for enzyme replacement with gene therapy in models of Parkinson’s disease},
  volume       = {2014:47},
  year         = {2014},
}