Assessment of GDNF in Primate Models of Parkinson's Disease: Comparison with Human Studies

Abstract

Potential future treatments for Parkinson's disease (PD) include those that not only provide symptomatic relief to patients but are also neuroprotective and/or neurorestorative. Glial cell line-derived neurotrophic factor (GDNF) may be a valuable candidate in this regard. Positive results using monkeys have encouraged the use of GDNF in human trials. These trials have unfortunately shown mixed results, illustrating the influence that various parameters of administration can have on clinical outcome. The aim of this review is to compare the findings of these clinical studies with available primate data. While bolus intraventricular injections of GDNF in primates have shown some behavioural efficacy, there was no clinical benefit in the first human trial using this method, which was most likely a result of inefficient GDNF distribution in the striatal parenchyma. In primates, however, continuous (rather than bolus) delivery of GDNF into the ventricles results in significant distribution in the striatum. While chronic delivery of GDNF into the ventricles has not been assessed in humans, intraputamenal protein delivery in two Phase I trials have demonstrated that GDNF considerably reduces PD symptoms, suggesting that the putamen is the optimal location for delivery. Primate studies have shown that vector mediated delivery of GDNF may provide a suitable means for long-term intraputamenal delivery. However, the possibility of high levels of GDNF resulting in widespread distribution of GDNF to non-targeted areas is a cause of concern, and vectors with transgene regulation are needed. The development of these vectors may be the way forward for GDNF treatment.

AAV2-mediated gene transfer of GDNF to the striatum of MPTP monkeys enhances the survival and outgrowth of co-implanted fetal dopamine neurons

“…In fact, clinical trials have been conducted to examine the effect of brain infusion of GDNF on clinical outcome in patients with Parkinson's disease. While some encouraging data emerged, side-effects were noted, which may have resulted from the high concentrations of GDNF delivered locally (Eslamboli, 2005;Kirik et al, 2004;Sherer et al, 2006). The use of viral vectors to deliver GDNF in a stable, and potentially a regulated manner, offers a more promising approach to protect remaining DA neurons in Parkinson's disease than direct infusions of GDNF (Kordower, 2003;McBride and Kordower, 2002).…”

NO-cGMP Signaling and Regenerative Medicine Involving Stem Cells

“…However, these trials have not resulted in any major long term improvement in patients. In the case of PD, conventional therapies including delivery of neurotrophic factors such as GDNF or other alternative therapies showed only limited short term success [30,105]. A second strategy involving transplantation of tissue from ventral mesencephalon also proved to be not greatly beneficial.…”

Neurogenesis as a potential therapeutic strategy for neurodegenerative diseases

“…GDNF has been shown to enhance the survival of dopaminergic neurons in animal models of PD and a few clinical trials [93]. Direct infusion of GDNF into the putamen of human PD patients demonstrated significant recovery of coordination-related activities, stimulated sprouting of tyrosine hydroxylase-positive neurons and increased dopamine storage even 2 years after the start of infusion [94,95].…”