Review of the Current Knowledge Base of the Topic

Direct intracerebral infusion of neurotrophic factors may represent a neuroprotective and neurorestorative therapeutic strategy for neurodegenerative movement disorders, most notably Parkinson’s disease (PD). A number of neurotrophins, including glial cell-line-derived neurotrophic factor (GDNF), neurteurin (NTN), cerebral dopamine neurotrophic factor (CDNF), and mesencephalic astrocyte-derived neurotrophic factor (MANF), are currently under preclinical and clinical investigation as infusional therapies for PD.

Infusion therapy has particular relevance to the treatment of PD, a common, debilitating, and incurable neurodegenerative disorder, because of a readily apparent “surgical target.” However, this strategy may also have application for the treatment of less common movement disorders, such as Huntington’s disease.

This chapter focuses on the preclinical and clinical evidence for the use of each of these four neurotrophins for the treatment of PD.

GDNF and NTN

GDNF and NTN are GDNF-family ligands, part of the transforming growth factor-β superfamily, a collection of multifunctional cytokines. Both neurotrophins have neuroprotective and neurorestorative effects in preclinical models of PD, leading to a number of early-phase clinical trials.

Preclinical Studies of GDNF and NTN Delivery for PD

The neuroprotective and neurorestorative effects of GDNF and NTN have largely been assessed in two validated preclinical models of PD: the 6-OHDA (6-hydroxydopamine) rodent model, and the MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) nonhuman primate (NHP) model.

Intraventricular Administration of GDNF and NTN in Rodents

Infusion of recombinant human GDNF and ¹²⁵ iodine-labeled GDNF ( ¹²⁵ I-GDNF) into the ventricular system of nonlesioned rats resulted in diffusion of GDNF into superficial and deep brain structures, including the cerebral cortex, septum, diagonal band of Broca, fimbria, striatum, hippocampus, hypothalamus, substantia nigra (SN), ventral tegmental area, and cerebellum. Immunohistochemical staining revealed significantly increased levels of dopamine in both the striatum and SN.

In a head-to-head comparison of intraventricular infusion of GDNF and NTN, NTN proved ineffective in providing neuroprotection or neurorestoration, which the authors consider may have been due to its poor solubility and diffusivity. The same study confirmed the protective and restorative effects of intraventricular GDNF.

However, intraventricular infusion of GDNF was also found to produce increased hypothalamic dopamine content, resulting in significant cachexia in experimental animals. Intraventricular infusion of GDNF in 6-OHDA-lesioned rats resulted in locomotor improvements and increased striatal dopamine turnover. Reduced weight gain remained a consistent adverse effect. The small volume of the rodent brain and proximity of structures to the ventricular system led to studies in NHPs.

Intraventricular Administration of GDNF and NTN in Nonhuman Primates

Intraventricular infusion of GDNF in MPTP-lesioned rhesus monkeys and marmosets has been associated with mixed results. Significant improvements in locomotor activity were demonstrated following four monthly infusions at doses ranging from 100 to 1000 μg of GDNF, which were correlated with increases in dopamine metabolite concentrations in the SN but not the putamen. Improvements in locomotor function and reductions in l -dopa-induced dyskinesia have also been observed in marmosets receiving intraventricular GDNF infusions.

Comparable success was demonstrated in an NHP study of intraventricular infusion of NTN 48 h prior to MPTP exposure. Compared to control, animals receiving NTN demonstrated significant neuroprotective effects, with some NHPs developing no locomotor evidence of Parkinsonism at all. The authors concluded that intraventricular NTN could protect dopaminergic neurons from degeneration, preventing the onset of Parkinsonian symptoms.

However, the limited translational potential of intraventricular infusion was brought into sharp focus by an autoradiographic study of the distribution of ¹²⁵ I-GDNF infused into the lateral ventricle of MPTP-lesioned rhesus monkeys, which demonstrated that GDNF did not diffuse effectively into the NHP caudate nucleus or putamen. This finding indicated that the success of intraventricular infusions in rodents might be a consequence of the much smaller diffusion distances within the rat brain. Furthermore, weight loss and dyskinesias remained recurrent complications in NHP studies.

Clinical Trials of Intraventricular Infusion of GDNF for PD

Despite the potential pitfalls associated with intraventricular infusion being apparent from NHP studies, the results of the first randomized double-blind placebo-controlled trial of intracerebroventricular infusion of GDNF were reported in 2003. This study comprised 50 patients with moderately advanced l -dopa-responsive PD. Unfortunately, the study failed to achieve its primary end point, as subjects reported substantial side-effects without evidence of clinical benefit. Side-effects included hyponatraemia, anorexia, weight loss, nausea, vomiting, and distressing Lhermitte’s phenomenon. Analysis of these findings led to the conclusion that inadequate diffusion of GDNF into nigrostriatal structures resulted in lack of clinical benefit, a finding corroborated by distribution studies in NHPs. This conclusion was supported by postmortem analysis of one of the trial subjects, which did not demonstrate evidence of dopaminergic neuronal recovery.

Localized Intraparenchymal Delivery of GDNF in Rodents

Intracerebral injection of GDNF into the SN or striatum at the time of 6-OHDA lesioning has been shown to be neuroprotective, and to be neurorestorative if delivered after lesioning. Intrastriatal delivery of GDNF offers advantages over intranigral administration by protecting the entire nigrostriatal pathway. Delivery of GDNF into the SN to target dopaminergic cell bodies does not protect striatal axons from degeneration and does not prevent locomotor disability, but is very effective at preventing cell death within the SN itself. Intrastriatal delivery of GDNF at the time of striatal lesioning does preserve motor function, however, suggesting that the effect of GDNF on dopaminergic neurons differs according to whether it is applied to axons or cell bodies. GDNF-induced functional improvements following severe 6-OHDA lesioning of the striatum are mediated by neurochemical changes in structures downstream from the striatum, including the globus pallidus interna and externa, as well as the SN.

Intraputamenal Delivery of GDNF and NTN in Nonhuman Primate Studies

The effects of continuous intraputamenal delivery of GDNF at doses ranging from 7.5 to 22.5 μg/day have been investigated in both normal aged and MPTP-lesioned NHPs. Histological correlates of GDNF effect include increased dopaminergic cell size and number within the SN, and increased fiber density throughout the striatum and globus pallidus. Biochemical correlates of GDNF effect include increases in dopamine and its metabolites in the striatum and globus pallidus. Intraputamenal infusions of GDNF in MPTP-lesioned primates and intact aged monkeys were associated with improvements in the primate PD rating scale, improved general motor performance, and increases in hand speed.

The neurorestorative potential of intraputamenal infusion of 30 μg/day NTN in MPTP-lesioned rhesus macaques was reported by Grondin et al., in . NTN-treated animals showed significant and sustained improvements in locomotor scores over a 3-month period when compared with placebo-infused controls. However, this study highlighted the variation in putamenal drug distribution, with volumes of distribution ranging from 27% to 93% of the entire putamen.