Cited by 297Parkinson's Disease Mechanisms and TreatmentsNerve injury and regenerationVirus-based gene therapy research

Intrastriatal injection of an adenoviral vector expressing glial-cell-line-derived neurotrophic factor prevents dopaminergic neuron degeneration and behavioral impairment in a rat model of Parkinson disease

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Bilang-Bleuel, Alicia, Revah, Frédéric, Colin, Phillippe, Locquet, Isabelle, Robert, Jean-Jacques, Mallet, Jacques, Horellou, Philippe·1997·Proceedings of the National Academy of Sciences

Abstract

Glial-cell-line-derived neurotrophic factor (GDNF) is a potent neurotrophic factor for adult nigral dopamine neurons in vivo . GDNF has both protective and restorative effects on the nigro-striatal dopaminergic (DA) system in animal models of Parkinson disease. Appropriate administration of this factor is essential for the success of its clinical application. Since it cannot cross the blood–brain barrier, a gene transfer method may be appropriate for delivery of the trophic factor to DA cells. We have constructed a recombinant adenovirus (Ad) encoding GDNF and injected it into rat striatum to make use of its ability to infect neurons and to be retrogradely transported by DA neurons. Ad-GDNF was found to drive production of large amounts of GDNF, as quantified by ELISA. The GDNF produced after gene transfer was biologically active: it increased the survival and differentiation of DA neurons in vitro . To test the efficacy of the Ad-mediated GDNF gene transfer in vivo , we used a progressive lesion model of Parkinson disease. Rats received injections unilaterally into their striatum first of Ad and then 6 days later of 6-hydroxydopamine. We found that mesencephalic nigral dopamine neurons of animals treated with the Ad-GDNF were protected, whereas those of animals treated with the Ad-β-galactosidase were not. This protection was associated with a difference in motor function: amphetamine-induced turning was much lower in animals that received the Ad-GDNF than in the animals that received Ad-β-galactosidase. This finding may have implications for the development of a treatment for Parkinson disease based on the use of neurotrophic factors.

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  • Intracerebral injections are clinically feasible and are performed in a variety of clinical scenarios and preclinical settings.

    “Intracerebral injections are clinically feasible, and are performed in a variety of clinical scenarios (17–23), as well as in various preclinical settings (4, 24–27).”

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Authors
Bilang-Bleuel, A., Revah, F., Colin, P., Locquet, I., Robert, J.-J., Mallet, J., & Horellou, P.
Affiliations
  • Unité Mixte de Recherche 9923, Centre National de la Recherche Scientifique, Laboratoire de Génétique Moléculaire de la Neurotransmission et des Processus Dégénératifs, Hôpital de la Pitié-Salpêtrière, Bâtiment CERVI, 83 Boulevard de l’Hôpital, 75013 Paris, France; and Rhône–Poulenc Rorer, GenCell, Centre de Recherches de Vitry-Alfortville, 13 Quai Jules Guesde, 94403 Vitry-sur-Seine, France
  • Centre National de la Recherche Scientifique (FR)
Venue
Proceedings of the National Academy of Sciences
Published
1997-08-05
Volume
94
Issue
16
Pages
8818-8823
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
OpenAlex
W2088827109
Cited by
297
References
1
Citations by year
2025: 1 · 2024: 1 · 2023: 1 · 2022: 2 · 2021: 1 · 2020: 5 · 2019: 4 · 2018: 4 · 2017: 1 · 2016: 2 · 2015: 5 · 2014: 4 · 2013: 3 · 2012: 4
FWCI
27.12
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
Keywords
glial cell line-derived neurotrophic factor, Parkinson's disease, adenoviral vector, gene therapy, dopaminergic neuron survival, striatum, 6-hydroxydopamine lesion, nigrostriatal pathway, neurotrophic factors, motor function
MeSH terms
Adenoviridae, Animals, Behavior, Animal, Disease Models, Animal, Female, Genetic Vectors, Nerve Growth Factors, Nerve Tissue Proteins, Neurons, Parkinson Disease, Genetic Therapy, Rats, Sprague-Dawley, Gene Transfer Techniques, Neuroprotective Agents, Glial Cell Line-Derived Neurotrophic Factor, Rats

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