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Development of lentiviral vectors for CNS gene transfer

Jakobsson, Johan LU orcid (2005)
Abstract
Gene therapy in the brain is a promising treatment strategy that in the future may be used for several brain disorders, including Parkinson's disease, Alzheimer's disease and lysosomal storage diseases. By introducing a new gene, rather than providing a classical pharmacological drug, gene therapy offers the opportunity to treat neurological disorders by a single intervention. However, gene therapy is dependent on efficient methods for transferring genes to the selected tissue. For this purpose, recombinant viruses have been developed. Some of these viral vectors, such as those based on lentivirus, adenovirus and adeno-associated virus, are able to provide stable and long-term in vivo gene transfer to the cells of the brain, including... (More)
Gene therapy in the brain is a promising treatment strategy that in the future may be used for several brain disorders, including Parkinson's disease, Alzheimer's disease and lysosomal storage diseases. By introducing a new gene, rather than providing a classical pharmacological drug, gene therapy offers the opportunity to treat neurological disorders by a single intervention. However, gene therapy is dependent on efficient methods for transferring genes to the selected tissue. For this purpose, recombinant viruses have been developed. Some of these viral vectors, such as those based on lentivirus, adenovirus and adeno-associated virus, are able to provide stable and long-term in vivo gene transfer to the cells of the brain, including neurons and glial cells.



The studies in this thesis are aimed at improving one type of these viral vectors, the HIV-I based lentiviral vectors. The experiments described in this thesis include the development and validation of lentiviral vectors capable of cell-type specific transgene expression and regulated transgene expression. A novel envelope pseudotype (Ross River virus glycoprotein) that could increase the biosafety of lentiviral vectors has also been investigated and was found to confer efficient gene transfer to neurons in vivo in the rat brain.



The results show that it is possible to construct improved lentiviral vectors for gene transfer in the brain. This have implications, not only for the use of lentiviral vectors in clinical gene transfer, but also for the use of these vectors in basic research and may contribute to an increased understanding of the brain and lead to the development of new treatment strategies. (Less)
Abstract (Swedish)
Popular Abstract in Swedish

Att leverera ett läkemedel till hjärnan är svårt då blod-hjärnbarriären effektivt stoppar de flesta kemiska substanser eller kräver att läkemedlet ges i höga systemiska doser. Om läkemedlet passerar blod-hjärnbärriaren påverkar det i så fall alla strukturer och celltyper. Detta är problematiskt i hjärnan då det här finns avgränsade strukturer med olika funktion, ibland till och med funktioner som motverkar varandra. Dessutom finns det flera olika celltyper i hjärnan, till exempel neuroner och astrocyter. Dessa olika celltyper har distinkta funktioner och samma drog kan ha olika effekt på dessa olika celltyper. Dessa problem leder i många fall till allvarliga biverkningar och har gjort användandet... (More)
Popular Abstract in Swedish

Att leverera ett läkemedel till hjärnan är svårt då blod-hjärnbarriären effektivt stoppar de flesta kemiska substanser eller kräver att läkemedlet ges i höga systemiska doser. Om läkemedlet passerar blod-hjärnbärriaren påverkar det i så fall alla strukturer och celltyper. Detta är problematiskt i hjärnan då det här finns avgränsade strukturer med olika funktion, ibland till och med funktioner som motverkar varandra. Dessutom finns det flera olika celltyper i hjärnan, till exempel neuroner och astrocyter. Dessa olika celltyper har distinkta funktioner och samma drog kan ha olika effekt på dessa olika celltyper. Dessa problem leder i många fall till allvarliga biverkningar och har gjort användandet av ett flertal lovande läkemedel omöjligt.En lösning på dessa problem skulle kunna vara genterapi. Genom att en terapeutisk gen levereras till en specifik celltyp i den önskade strukturen skulle man kunna undvika ovanstående problem.



För att genterapi i hjärnan ska kunna fungera krävs det att man utvecklar effektiva metoder för att överföra gener. För detta syfte har omgjorda virus utvecklats. Dessa virus, eller så kallade virala vektorer, behåller förmågan att överföra gener till andra celler men har blivit modifierade så att de inte kan föröka sig och sprida sjukdomar. I denna avhandling har en typ av viral vektor, baserad på HIV-virus, byggts om så att en mer effektiv och säker genterapi är möjlig. Genom att ändra om i virusets genetiska kod så har genterapivektorer som kan styras till specifika celltyper utvecklats och validerats. Dessutom har vektorer i vilka dosen av den nya genens effekt kan regleras utvecklats och testats. Dessa experiment har varit framgångsrika och visar att det är möjligt att konstruera genterapivektorer för användning i hjärnan som är både effektiva och säkra. Dessa framsteg kan bidra till att HIV-baserade genterapivektorer kommer att användas för att behandla olika hjärnsjukdomar såsom Parkinsons och Alzheimers sjukdom. Dessutom kan dessa vektorer användas inom biomedicinsk forskning för att öka förståelsen för hur hjärnan fungerar, något som i slutändan kommer att leda till utvecklandet av nya läkemedel. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Dr. Déglon, Nicole, Atomic Energy Commision, Department of Medical Research, Orsay Cedex, France
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Medicin (människa och djur), Medicine (human and vertebrates), Biotechnology, Gene Therapy, Neurological disorders
pages
134 pages
publisher
Johan Jakobsson
defense location
Segerfalksalen Biomedicinskt Centrum Sölvegatan 17 Lund
defense date
2005-09-23 09:15:00
ISBN
91-85439-78-9
language
English
LU publication?
yes
additional info
Johan Jakobsson, Cecilia Ericson, Maria Jansson, Elin Björk and Cecilia Lundberg. 2003. Targeted transgene expression in the rat brain using lentiviral vectors Journal of Neuroscience Research, vol 73 pp 876-885.
Johan Jakobsson, Biljana Georgievska, Cecilia Ericson and Cecilia Lundberg. 2004. Lesion-dependent regulation of transgene expression in the rat brain using a human glial fibrillary acidic protein-lentiviral vector European Journal of Neuroscience, vol 19 pp 761-765.
Biljana Georgievska, Johan Jakobsson, Elisabeth Persson, Deniz Kirik and Cecilia Lundberg. 2004. Regulated delivery of glial cell line-derived neurotrophic factor into the rat striatum, using a tetracycline-dependent lentiviral vector Human Gene Therapy, vol 15 pp 934-944.
Johan Jakobsson, Nina Rosenqvist and Cecilia Lundberg. . Cell-type specific and auto-regulated gene transfer to reactive astrocytes in lesion models of rat brain using lentiviral vectors (submitted)
Johan Jakobsson, Nina Rosenqvist, Karl Mårild, Denes v. Agoston and Cecilia Lundberg. . A rat enkephalin promoter in a lentiviral vector confers appropriate regulation of transgene expression in a model of Parkinson's disease (submitted)
Johan Jakobsson, Troels Tolstrup Nielsen, Karin Stafflin, Biljana Georgievska and Cecilia Lundberg. . Efficient Transduction of Neurons using Ross River Glycoprotein-Pseudotyped Lentiviral Vectors (submitted)
id
594c7d80-527c-4247-a56d-00a8454be518 (old id 545284)
date added to LUP
2016-04-01 16:20:29
date last changed
2019-04-13 02:18:19
@phdthesis{594c7d80-527c-4247-a56d-00a8454be518,
  abstract     = {{Gene therapy in the brain is a promising treatment strategy that in the future may be used for several brain disorders, including Parkinson's disease, Alzheimer's disease and lysosomal storage diseases. By introducing a new gene, rather than providing a classical pharmacological drug, gene therapy offers the opportunity to treat neurological disorders by a single intervention. However, gene therapy is dependent on efficient methods for transferring genes to the selected tissue. For this purpose, recombinant viruses have been developed. Some of these viral vectors, such as those based on lentivirus, adenovirus and adeno-associated virus, are able to provide stable and long-term in vivo gene transfer to the cells of the brain, including neurons and glial cells.<br/><br>
<br/><br>
The studies in this thesis are aimed at improving one type of these viral vectors, the HIV-I based lentiviral vectors. The experiments described in this thesis include the development and validation of lentiviral vectors capable of cell-type specific transgene expression and regulated transgene expression. A novel envelope pseudotype (Ross River virus glycoprotein) that could increase the biosafety of lentiviral vectors has also been investigated and was found to confer efficient gene transfer to neurons in vivo in the rat brain.<br/><br>
<br/><br>
The results show that it is possible to construct improved lentiviral vectors for gene transfer in the brain. This have implications, not only for the use of lentiviral vectors in clinical gene transfer, but also for the use of these vectors in basic research and may contribute to an increased understanding of the brain and lead to the development of new treatment strategies.}},
  author       = {{Jakobsson, Johan}},
  isbn         = {{91-85439-78-9}},
  keywords     = {{Medicin (människa och djur); Medicine (human and vertebrates); Biotechnology; Gene Therapy; Neurological disorders}},
  language     = {{eng}},
  publisher    = {{Johan Jakobsson}},
  school       = {{Lund University}},
  title        = {{Development of lentiviral vectors for CNS gene transfer}},
  year         = {{2005}},
}