Development of lentiviral vectors for CNS gene transfer

Sammanfattning: 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.