GDNF-mediated rescue of the nigrostriatal system depends on the degree of degeneration
Gene Ther. 2018-12-07; 26(1-2): 57-64
DOI: 10.1038/s41434-018-0049-0
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1. Gene Ther. 2019 Feb;26(1-2):57-64. doi: 10.1038/s41434-018-0049-0. Epub 2018 Dec
7.
GDNF-mediated rescue of the nigrostriatal system depends on the degree of
degeneration.
Quintino L(1), Avallone M(1), Brännstrom E(1), Kavanagh P(1), Lockowandt M(1),
Garcia Jareño P(1), Breger LS(1), Lundberg C(2).
Author information:
(1)CNS Gene Therapy, Department of Experimental Medical Science, Lund University,
Lund, Sweden.
(2)CNS Gene Therapy, Department of Experimental Medical Science, Lund University,
Lund, Sweden. .
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.
DOI: 10.1038/s41434-018-0049-0
PMID: 30531868