Direct brain infusion of glial cell line–derived neurotrophic factor in Parkinson disease

Abstract

Glial cell line-derived neurotrophic factor (GDNF) is a potent neurotrophic factor with restorative effects in a wide variety of rodent and primate models of Parkinson disease, but penetration into brain tissue from either the blood or the cerebro-spinal fluid is limited. Here we delivered GDNF directly into the putamen of five Parkinson patients in a phase 1 safety trial. One catheter needed to be repositioned and there were changes in the magnetic resonance images that disappeared after lowering the concentration of GDNF. After one year, there were no serious clinical side effects, a 39% improvement in the off-medication motor sub-score of the Unified Parkinson's Disease Rating Scale (UPDRS) and a 61% improvement in the activities of daily living sub-score. Medication-induced dyskinesias were reduced by 64% and were not observed off medication during chronic GDNF delivery. Positron emission tomography (PET) scans of [(18)F]dopamine uptake showed a significant 28% increase in putamen dopamine storage after 18 months, suggesting a direct effect of GDNF on dopamine function. This study warrants careful examination of GDNF as a treatment for Parkinson disease.

Viral vector delivery of neurotrophic factors for Parkinson's disease therapy

“…Initial clinical trials involved administering GDNF protein, with mixed results ( Refs 37,38,39,40,41,42). The appearance of GDNF antibodies in some patients (Refs 41, 42) highlighted a need to approach NTF therapy differently.…”

Neurotrophic factors for the treatment of Parkinson's disease

“…Promising results emerged from two open-label trials, which used intraputaminal infusion of recombinant GDNF [126][127][128][129]. These trials both reported improvements in the patients' motor symptoms and in activities of daily living, without any serious side-effects.…”

“…In both studies, the only consistent adverse effect was a mild l'Hermitte's sign. Improvements in dopamine storage were detected in the regions surrounding the catheter which was used for infusion of GDNF [126,127].…”

Shedding light into the role of BDNF in the pharmacotherapy of Parkinson's disease

“…For instance, GDNF is a neurotrophic factor with restorative effects in rodent and primate models of PD. 53 In addition, we have shown that the dopamine D2 agonist quinpirole enhances the expression of basic fibroblast growth factor (FGF-2), 54 a trophic factor whose action is essential for the survival of dopaminergic neurons. 55,56 Thus, drugs used against PD might also regulate other trophic factors, probably affording a higher degree of neuroprotection through a combined action.…”