Neuroprotective Effect of a CNTF-Expressing Lentiviral Vector in the Quinolinic Acid Rat Model of Huntington's Disease
Neurodegenerative diseases represent promising targets for gene therapy approaches provided effective transfer vectors. In the present study, we evaluated the effectiveness of LacZ-expressing lentiviral vectors with two different internal promoters, the mouse phosphoglycerate kinase 1 (PGK) and cyto...
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| Format: | Article |
| Language: | English |
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Elsevier
2001-06-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996101903882 |
| _version_ | 1818565774810284032 |
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| author | L.Pereira de Almeida D. Zala P. Aebischer N. Déglon |
| author_facet | L.Pereira de Almeida D. Zala P. Aebischer N. Déglon |
| author_sort | L.Pereira de Almeida |
| collection | DOAJ |
| description | Neurodegenerative diseases represent promising targets for gene therapy approaches provided effective transfer vectors. In the present study, we evaluated the effectiveness of LacZ-expressing lentiviral vectors with two different internal promoters, the mouse phosphoglycerate kinase 1 (PGK) and cytomegalovirus (CMV), to infect striatal cells. The intrastriatal injection of lenti-β-Gal vectors lead to 207, 400 ± 11,500 and 303,100 ± 4,300 infected cells in adult rats, respectively. Importantly, the β-galactosidase activity was higher in striatal extracts from PGK-LacZ-injected animals as compared to CMV-LacZ animals. The efficacy of the system was further examined with a potential therapeutic gene for the treatment of Huntington's disease, the human ciliary neurotrophic factor (CNTF). PGK-LacZ- or PGK-CNTF-expressing viruses were stereotaxically injected into the striatum of rats, 3 weeks later the animals were unilaterally lesioned with 180 nmol of quinolinic acid (QA). Control animals displayed 148 ± 43 apomorphine-induced rotations ipsilateral to the lesion 5 days postlesion as compared to 26 ± 22 turns/45 min in the CNTF-treated group. The extent of the striatal damage was significantly diminished in the CNTF-treated rats as indicated by the 52 ± 9.7% decrease of the lesion volume and the sparing of DARPP-32, ChAT and NADPH-d neuronal populations. These results further establish that lentiviruses may represent an efficient gene delivery system for the screening of therapeutic molecules in Huntington's disease. |
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| id | doaj.art-2155ee2009534cf89a29693e48bdf045 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-14T01:45:19Z |
| publishDate | 2001-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-2155ee2009534cf89a29693e48bdf0452022-12-21T23:21:35ZengElsevierNeurobiology of Disease1095-953X2001-06-0183433446Neuroprotective Effect of a CNTF-Expressing Lentiviral Vector in the Quinolinic Acid Rat Model of Huntington's DiseaseL.Pereira de Almeida0D. Zala1P. Aebischer2N. Déglon3Division of Surgical Research and Gene Therapy Center, Lausanne Medical School, Switzerland; Laboratory of Pharmaceutical Technology, Faculty of Pharmacy and Center for Neuroscience, University of Coimbra, Portugal; Swiss Federal Institute of Technology, EPFL, Lausanne, SwitzerlandDivision of Surgical Research and Gene Therapy Center, Lausanne Medical School, Switzerland; Laboratory of Pharmaceutical Technology, Faculty of Pharmacy and Center for Neuroscience, University of Coimbra, Portugal; Swiss Federal Institute of Technology, EPFL, Lausanne, SwitzerlandDivision of Surgical Research and Gene Therapy Center, Lausanne Medical School, Switzerland; Laboratory of Pharmaceutical Technology, Faculty of Pharmacy and Center for Neuroscience, University of Coimbra, Portugal; Swiss Federal Institute of Technology, EPFL, Lausanne, SwitzerlandDivision of Surgical Research and Gene Therapy Center, Lausanne Medical School, Switzerland; Laboratory of Pharmaceutical Technology, Faculty of Pharmacy and Center for Neuroscience, University of Coimbra, Portugal; Swiss Federal Institute of Technology, EPFL, Lausanne, SwitzerlandNeurodegenerative diseases represent promising targets for gene therapy approaches provided effective transfer vectors. In the present study, we evaluated the effectiveness of LacZ-expressing lentiviral vectors with two different internal promoters, the mouse phosphoglycerate kinase 1 (PGK) and cytomegalovirus (CMV), to infect striatal cells. The intrastriatal injection of lenti-β-Gal vectors lead to 207, 400 ± 11,500 and 303,100 ± 4,300 infected cells in adult rats, respectively. Importantly, the β-galactosidase activity was higher in striatal extracts from PGK-LacZ-injected animals as compared to CMV-LacZ animals. The efficacy of the system was further examined with a potential therapeutic gene for the treatment of Huntington's disease, the human ciliary neurotrophic factor (CNTF). PGK-LacZ- or PGK-CNTF-expressing viruses were stereotaxically injected into the striatum of rats, 3 weeks later the animals were unilaterally lesioned with 180 nmol of quinolinic acid (QA). Control animals displayed 148 ± 43 apomorphine-induced rotations ipsilateral to the lesion 5 days postlesion as compared to 26 ± 22 turns/45 min in the CNTF-treated group. The extent of the striatal damage was significantly diminished in the CNTF-treated rats as indicated by the 52 ± 9.7% decrease of the lesion volume and the sparing of DARPP-32, ChAT and NADPH-d neuronal populations. These results further establish that lentiviruses may represent an efficient gene delivery system for the screening of therapeutic molecules in Huntington's disease.http://www.sciencedirect.com/science/article/pii/S0969996101903882Huntington's diseaselentiviral vectorgene therapyciliary neurotrophic factorquinolinic acid lesion model |
| spellingShingle | L.Pereira de Almeida D. Zala P. Aebischer N. Déglon Neuroprotective Effect of a CNTF-Expressing Lentiviral Vector in the Quinolinic Acid Rat Model of Huntington's Disease Neurobiology of Disease Huntington's disease lentiviral vector gene therapy ciliary neurotrophic factor quinolinic acid lesion model |
| title | Neuroprotective Effect of a CNTF-Expressing Lentiviral Vector in the Quinolinic Acid Rat Model of Huntington's Disease |
| title_full | Neuroprotective Effect of a CNTF-Expressing Lentiviral Vector in the Quinolinic Acid Rat Model of Huntington's Disease |
| title_fullStr | Neuroprotective Effect of a CNTF-Expressing Lentiviral Vector in the Quinolinic Acid Rat Model of Huntington's Disease |
| title_full_unstemmed | Neuroprotective Effect of a CNTF-Expressing Lentiviral Vector in the Quinolinic Acid Rat Model of Huntington's Disease |
| title_short | Neuroprotective Effect of a CNTF-Expressing Lentiviral Vector in the Quinolinic Acid Rat Model of Huntington's Disease |
| title_sort | neuroprotective effect of a cntf expressing lentiviral vector in the quinolinic acid rat model of huntington s disease |
| topic | Huntington's disease lentiviral vector gene therapy ciliary neurotrophic factor quinolinic acid lesion model |
| url | http://www.sciencedirect.com/science/article/pii/S0969996101903882 |
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