Brain, Vol. 125, No. 10, 2149-2151,
October 2002
© 2002 Oxford University Press
Editorial |
GDNF treatment in Parkinson’s disease: time for controlled clinical trials?
Department of Physiological Sciences Lund University, Sweden
Restorative treatments for brain disorders are rare. In neuroscience research, it is not uncommon to suggest that experimental treatment strategies may have great clinical potential. The rescue or regeneration of a few cultured neurones may be sufficient to entice such optimism. However, the path to a new clinical therapy is typically painstakingly long and difficult to navigate. In our minds, we would like it always to be a straight path starting with tests in cell models and rodents providing us with mechanisms of action and leading to trials in non-human primates. Then open-label tests can be performed in small patient groups and eventually large controlled clinical trials are conducted. In reality, however, the path may be tortuous, filled with detours that set the field back, as well as shortcuts and parallel tracks that yield different strategies which develop at their own speed. The development of glial cell line-derived neurotrophic factor (GDNF) as a treatment for tgciq’s disease over the past nine years provides an example of such an interesting journey. Moreover, it illustrates one role of non-human primates in preclinical development of a novel therapy.
In this issue, Grondin and co-workers (Grondin et al., 2002
) present evidence for structural and functional benefits of infusions of GDNF in rhesus monkeys previously rendered parkinsonian by unilateral intracarotid injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Using mini-pumps, they infused 5–15 µg/day GDNF either into the lateral ventricle or the dopamine-depleted dorsal putamen. Starting during the first month, there was a gradual and marked reduction in parkinsonian symptoms, including bradykinesia and rigidity, without any signs of adverse effects. Post-mortem examination revealed partial restoration of dopamine and its metabolites in the corpus striatum, as well as evidence for an increased number of nigrostriatal dopaminergic fibres and cell bodies in the substantia nigra. Interestingly, there were no significant differences between the intraventricular- and intraputamenal-infusion groups, so the data for both groups were pooled. This is the first demonstration that GDNF infused directly into the brain parenchyma of non-human primates is effective in restoring dopaminergic function. The treatment was not initiated until over 3 months after the MPTP lesion, when most of the dopaminergic cells had probably died due to the toxin. Therefore the authors argue that GDNF most likely worked through a neuroregenerative mechanism as opposed to one of acute neuroprotection (Grondin et al., 2002).
Since the discovery of GDNF in 1993 (Lin et al., 1993) numerous cell culture experiments and rodent studies have demonstrated that it is active on different cell types in multiple tissues. GDNF is a particularly potent factor for survival and axonal growth of mesencephalic dopaminergic neurones and has been shown to ameliorate motor deficits and reduce brain damage in several animal models of tgciq’s disease (Björklund et al., 1997, 2000; Gash et al., 1996; Kordower et al., 2000; Zurn et al., 2001). Strategies for delivery have been diverse and include intermittent injections; continuous infusions; release from encapsulated genetically engineered cells; and gene transfer via viral vectors injected into the brain. In one recent and particularly pertinent study, Kordower et al. (2000) used a lentiviral vector to induce GDNF production in the striatum and demonstrated functional and structural recovery when initiating treatment one week after a systemic MPTP lesion in monkeys. While that study does not exclude an effect on axonal sprouting, it is also consistent with the possibility of a neuroprotective action of GDNF, since the lesion is not completely developed after one week.
Despite extensive study, the mechanism of action of GDNF in cell and animal models of Parkinson’s disease is far from fully elucidated. In dopaminergic neurones, GDNF binds to the 
1-subtype of GDNF family cell surface receptors (GDF-1; Airaksinen and Saarma, 2002). The receptors signal through receptor tyrosine kinase (RET), and can thereby phosphorylate different intracellular targets. In animal and cell culture experiments, it is conceivable that GDNF signaling protects against the acute effects of toxins, revives already injured neurones, promotes axonal regeneration, or is able to exert all of these effects. Understanding possible mechanisms of action of GDNF in the diseased human brain is truly of tremendous importance for possible future treatment of Parkinson’s disease. Interestingly, the significant recovery in behaviour in the study by Grondin and co-workers is paralleled by only a small increase in mean striatal dopamine levels from 3 to 
10% of normal (Grondin et al., 2002), suggesting that GDNF may induce additional functional plasticity in the basal ganglia beyond mere increases in dopamine synthesis. An additional intriguing feature is that the number of nigral neurones expressing the dopamine-synthesizing enzyme tyrosine hydroxylase (TH) increased by 80%. It should be noted, however, that in absolute numbers the increase in TH-immunopositive neurones is relatively small, i.e. from around 35 000 to almost 65 000 on the lesioned side, compared to a normal value around 200 000 (Grondin et al., 2002). The authors suggest that GDNF may affect TH expression levels in neurones that were injured, but not killed, by the MPTP insult. However, as mentioned earlier, the GDNF was administered at least 3 months after the MPTP lesion. By then one might expect neurones to have either died or, if only injured, to already have regained their full capacity to produce TH. The authors did not discuss whether the increased number of TH-immunopositive neurones could be the result of another exciting possibility, namely neurogenesis in the adult brain. Generation of new neurones is now generally accepted to contribute to the neuronal population in certain adult brain regions, e.g. the hippocampus and olfactory bulb (Temple, 2001). Whether it also occurs in other brain regions in the uninjured adult brain is controversial, but accumulating evidence indicates that forebrain neurogenesis is stimulated by brain lesions (Arvidsson et al., 2002; Magavi et al., 2000) and by intraventricular infusion of growth factors (Fallon et al., 2000; Pencea et al., 2001), and may even support recovery of function (Nakatomi et al., 2002). A recent study demonstrated newly generated cells in the adult rat substantia nigra (Lie et al., 2002). While the study indicated that they primarily develop into glial cells, observations from others suggest that there is genesis of nigrostriatal dopaminergic neurones in mice which is promoted by MPTP lesions (Zhao et al., 2001). It has even been discussed that a disease such as Parkinson’s disease, which classically is considered neurodegenerative in nature, may in fact be due to failure of the birth, differentiation, migration or integration of new neurones that normally should replace those dying due to normal ageing (Armstrong and Barker, 2001). Whether GDNF treatment in animals or humans with reduced numbers of nigral dopaminergic neurones could promote a ‘self-repair’ process will be an exciting area of future investigation.
Interestingly, there have already been clinical tests with GDNF administration in Parkinson’s disease patients. So far, the only published report describes one single case from a larger cohort of patients in a safety and tolerability trial (Kordower et al., 1999). It recounts post-mortem findings in a late stage patient who was treated with monthly intraventricular injections of GDNF into the ventricle for 14 months, 23 years after the onset of Parkinson’s disease symptoms. There were no reductions of parkinsonian symptoms in this patient and no evidence of structural repair in the brain. Instead this patient developed several unwanted side effects, including nausea, loss of appetite, cutaneous sensory disturbances and psychiatric symptoms. Possibly high bolus doses spreading GDNF throughout the nervous system via the cerebrospinal fluid contributed to the unwanted side effects. Also the intermittent, as opposed to continuous, delivery may have been a disadvantage. In addition, there is some preliminary evidence from an unpublished open-label trial in five Parkinson’s disease patients performed in the UK that direct GDNF delivery into the putamen may be a better alternative. At the 54th American Academy for Neurology Meeting 2002, Dr Steven S. Gill (Bristol, UK) described the clinical outcome of a one-year human recombinant GDNF treatment in these patients (Gill et al., 2002). According to a report from the conference, there was a substantial reduction in the Unified Parkinson’s Disease Rating Scale from 66 to 30 (Robinson, 2002). There was no evidence of side effects of the nature observed in the US study by Kordower et al. (1999). These results are highly interesting and promising. They also highlight that the route of administration and dose of growth factors can be decisive determinants for a successful outcome and that it may be unwise to be overly pessimistic from initial negative clinical results.
Although the study by Grondin et al. (2002) is not the first to evaluate the effects of GDNF injections in MPTP-treated monkeys (Gash et al., 1996), it adds important information regarding GDNF dosage. Notably, clinical trials were performed in Parkinson’s disease patients already before these primate experiments were available. This raises the question of how experiments in non-human primates keep us on the ideal path from the cell culture dish to novel clinical restorative treatments for Parkinson’s disease. Due to expense, practical difficulties and the ethical issues associated with use of monkeys for experimental brain surgery, only a small number of such experiments can ever be conducted for each treatment strategy. Therefore they are unlikely to provide detailed insight into mechanisms of action. Moreover, as monkey models of Parkinson’s disease are at best analogies of the clinical disease and its underlying pathogenesis, treatment trials in monkeys can only provide us with educated guesses regarding whether the strategies will be effective in Parkinson’s disease patients. The main assets of monkey experiments may be in generating information on how to scale up from the small rodent brain to the large human brain. They can assist in predicting what doses, injection sites, delivery methods and administration schemes may be optimal for a growth factor to diffuse and provide its cellular targets with bioactive concentrations. Moreover, they may help us predict unwanted side effects. However, there is no doubt that careful clinical trials are of paramount importance when the time is ripe. Currently, it is not clear whether additional monkey experiments are needed before a GDNF injection protocol for systematic testing in humans can be developed. When more information is made available from the pilot study with intraputamenal GDNF infusions performed in the UK, it may be time to consider a controlled clinical trial in a limited number of Parkinson’s disease patients.
Patrik Brundin
Department of Physiological Sciences
Lund University, Sweden
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