GDNF supports function and survival of dopamine neurons that degenerate in Parkinson’s disease (PD). Ectopic delivery of GDNF in clinical trials to treat PD is safe but lacks significant therapeutic effect. In pre-clinical models, ectopic GDNF is effective but causes adverse effects including downregulation of tyrosine hydroxylase, only a transient boost in dopamine metabolism, aberrant neuronal sprouting and hyperactivity. Hindering development of GDNF mimetic, increased signalling via GDNF receptor RET by activating mutations results in cancer. To develop successful GDNF-based therapies, safe and effective mode of action must be defined first in animal models. Previously we showed that about a two-fold increase in endogenous GDNF expression is safe and results in increased motor and dopaminergic function and protection in PD model in young animals. Recently, similar results were reported using a novel Gdnf mRNA-targeting strategy. Next, it is important to establish safety of long-term increase in endogenous GDNF expression. We report behavioural, dopamine system and cancer analysis of five cohorts of aged mice with two-fold increase in endogenous GDNF. We found sustained increase in dopamine levels, improvement in motor learning and no side-effects or cancer. These results support rationale for further development of endogenous GDNF-based treatments and GDNF mimetic.
Original languageEnglish
JournalMolecular therapy-Methods & clinical development
Pages (from-to)831-842
Number of pages12
Publication statusPublished - 11 Apr 2020
MoE publication typeA1 Journal article-refereed

Fields of Science

  • GDNF
  • safety evaluation
  • motor function
  • dopamine system
  • long-term side-effects
  • 3111 Biomedicine

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