Chronic 2-Fold Elevation of Endogenous GDNF Levels Is Safe and Enhances Motor and Dopaminergic Function in Aged Mice

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Turconi , G , Kopra , J , Võikar , V , Kulesskaya , N , Vilenius , C , Piepponen , T P & Andressoo , J-O 2020 , ' Chronic 2-Fold Elevation of Endogenous GDNF Levels Is Safe and Enhances Motor and Dopaminergic Function in Aged Mice ' , Molecular therapy-Methods & clinical development , vol. 17 , pp. 831-842 . https://doi.org/10.1016/j.omtm.2020.04.003

Title: Chronic 2-Fold Elevation of Endogenous GDNF Levels Is Safe and Enhances Motor and Dopaminergic Function in Aged Mice
Author: Turconi, Giorgio; Kopra, Jaakko; Võikar, Vootele; Kulesskaya, Natalia; Vilenius, Carolina; Piepponen, T. Petteri; Andressoo, Jaan-Olle
Contributor: University of Helsinki, Department of Pharmacology
University of Helsinki, Regenerative pharmacology group
University of Helsinki, Biosciences
University of Helsinki, Biosciences
University of Helsinki, Institute of Biotechnology
University of Helsinki, Regenerative pharmacology group
University of Helsinki, Medicum
Date: 2020-06-12
Language: eng
Number of pages: 12
Belongs to series: Molecular therapy-Methods & clinical development
ISSN: 2329-0501
URI: http://hdl.handle.net/10138/316712
Abstract: Glial cell line-derived neurotrophic factor (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 signaling via GDNF receptor RET by activating mutations results in cancer. Safe and effective mode of action must be defined first in animal models to develop successful GDNF-based therapies. Previously we showed that about a 2-fold increase in endogenous GDNF expression is safe and results in increased motor and dopaminergic function and protection in a PD model in young animals. Recently, similar results were reported using a novel Gdnf mRNA-targeting strategy. Next, it is important to establish the safety of a long-term increase in endogenous GDNF expression. We report behavioral, dopamine system, and cancer analysis of five cohorts of aged mice with a 2-fold increase in endogenous GDNF. We found a sustained increase in dopamine levels, improvement in motor learning, and no side effects or cancer. These results support the rationale for further development of endogenous GDNF-based treatments and GDNF mimetic.
Subject: 3111 Biomedicine
GDNF
safety evaluation
motor function
dopamine system
long-term side-effects
TYROSINE-HYDROXYLASE
MOUSE
DOWN-REGULATION
RECEPTOR
INFUSION
OVEREXPRESSION
NEUROTROPHIC FACTOR GDNF
NEURONS
DEFICITS
EXPRESSION
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