Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

GDNF-mediated rescue of the nigrostriatal system depends on the degree of degeneration

Quintino, Luis LU orcid ; Avallone, Martino LU ; Brännstrom, Emil LU ; Kavanagh, Patrick LU ; Lockowandt, Marcus LU ; Garcia Jareño, Patricia ; Breger, Ludivine S. LU and Lundberg, Cecilia LU orcid (2019) In Gene Therapy 26(1-2). p.57-64
Abstract

Glial cell-line derived neurotrophic factor (GDNF) is a promising therapeutic molecule to treat Parkinson’s disease. Despite an excellent profile in experimental settings, clinical trials testing GDNF have failed. One of the theories to explain these negative outcomes is that the clinical trials were done in late-stage patients that have advanced nigrostriatal degeneration and may therefore not respond to a neurotrophic factor therapy. Based on this idea, we tested if the stage of nigrostriatal degeneration is important for GDNF-based therapies. Lentiviral vectors expressing regulated GDNF were delivered to the striatum of rats to allow GDNF expression to be turned on either while the nigrostriatal system was degenerating or after the... (More)

Glial cell-line derived neurotrophic factor (GDNF) is a promising therapeutic molecule to treat Parkinson’s disease. Despite an excellent profile in experimental settings, clinical trials testing GDNF have failed. One of the theories to explain these negative outcomes is that the clinical trials were done in late-stage patients that have advanced nigrostriatal degeneration and may therefore not respond to a neurotrophic factor therapy. Based on this idea, we tested if the stage of nigrostriatal degeneration is important for GDNF-based therapies. Lentiviral vectors expressing regulated GDNF were delivered to the striatum of rats to allow GDNF expression to be turned on either while the nigrostriatal system was degenerating or after the nigrostriatal system had been fully lesioned by 6-OHDA. In the group of animals where GDNF expression was on during degeneration, neurons were rescued and there was a reversal of motor deficits. Turning GDNF expression on after the nigrostriatal system was lesioned did not rescue neurons or reverse motor deficits. In fact, these animals were indistinguishable from the control groups. Our results suggest that GDNF can reverse motor deficits and nigrostriatal pathology despite an ongoing nigrostriatal degeneration, if there is still a sufficient number of remaining neurons to respond to therapy.

(Less)
Please use this url to cite or link to this publication:
author
; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Gene Therapy
volume
26
issue
1-2
pages
57 - 64
publisher
Nature Publishing Group
external identifiers
  • scopus:85058121882
  • pmid:30531868
ISSN
0969-7128
DOI
10.1038/s41434-018-0049-0
language
English
LU publication?
yes
id
c318ce53-bd9d-4ee9-ab19-f94a2a55abc6
date added to LUP
2019-01-02 09:08:11
date last changed
2024-10-29 15:28:00
@article{c318ce53-bd9d-4ee9-ab19-f94a2a55abc6,
  abstract     = {{<p>Glial cell-line derived neurotrophic factor (GDNF) is a promising therapeutic molecule to treat Parkinson’s disease. Despite an excellent profile in experimental settings, clinical trials testing GDNF have failed. One of the theories to explain these negative outcomes is that the clinical trials were done in late-stage patients that have advanced nigrostriatal degeneration and may therefore not respond to a neurotrophic factor therapy. Based on this idea, we tested if the stage of nigrostriatal degeneration is important for GDNF-based therapies. Lentiviral vectors expressing regulated GDNF were delivered to the striatum of rats to allow GDNF expression to be turned on either while the nigrostriatal system was degenerating or after the nigrostriatal system had been fully lesioned by 6-OHDA. In the group of animals where GDNF expression was on during degeneration, neurons were rescued and there was a reversal of motor deficits. Turning GDNF expression on after the nigrostriatal system was lesioned did not rescue neurons or reverse motor deficits. In fact, these animals were indistinguishable from the control groups. Our results suggest that GDNF can reverse motor deficits and nigrostriatal pathology despite an ongoing nigrostriatal degeneration, if there is still a sufficient number of remaining neurons to respond to therapy.</p>}},
  author       = {{Quintino, Luis and Avallone, Martino and Brännstrom, Emil and Kavanagh, Patrick and Lockowandt, Marcus and Garcia Jareño, Patricia and Breger, Ludivine S. and Lundberg, Cecilia}},
  issn         = {{0969-7128}},
  language     = {{eng}},
  number       = {{1-2}},
  pages        = {{57--64}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Gene Therapy}},
  title        = {{GDNF-mediated rescue of the nigrostriatal system depends on the degree of degeneration}},
  url          = {{http://dx.doi.org/10.1038/s41434-018-0049-0}},
  doi          = {{10.1038/s41434-018-0049-0}},
  volume       = {{26}},
  year         = {{2019}},
}