Extended Treatment with Glial Cell Line-Derived Neurotrophic Factor in Parkinson’s Disease

Abstract

Background: Intraputamenal glial cell line-derived neurotrophic factor (GDNF), administered every 4 weeks to patients with moderately advanced Parkinson's disease, did not show significant clinical improvements against placebo at 40 weeks, although it significantly increased [ 18 F]DOPA uptake throughout the entire putamen. Objective: This open-label extension study explored the effects of continued (prior GDNF patients) or new (prior placebo patients) exposure to GDNF for another 40 weeks. Methods: Using the infusion protocol of the parent study, all patients received GDNF without disclosing prior treatment allocations (GDNF or placebo). The primary outcome was the percentage change from baseline to Week 80 in the OFF state Unified Parkinson's Disease Rating Scale (UPDRS) motor score. Results: All 41 parent study participants were enrolled. The primary outcome decreased by 26.7 ± 20.7% in patients on GDNF for 80 weeks (GDNF/GDNF; N = 21) and 27.6 ± 23.6% in patients on placebo for 40 weeks followed by GDNF for 40 weeks (placebo/GDNF, N = 20; least squares mean difference: 0.4%, 95% CI:-13.9, 14.6, p = 0.96). Secondary endpoints did not show significant differences between the groups at Week 80 either. Prespecified comparisons between GDNF/GDNF at Week

Trial of magnetic resonance–guided putaminal gene therapy for advanced Parkinson's disease

“…Our study used an AAV2 vector encoding GDNF. Whone and colleagues recently reported a blinded clinical study of CED delivering intraputaminal GDNF protein versus placebo in PD patients . GDNF infusion was safe and well tolerated.…”

“…Whone and colleagues recently reported a blinded clinical study of CED delivering intraputaminal GDNF protein versus placebo in PD patients. 24,25 GDNF infusion was safe and well tolerated. Furthermore, the group receiving GDNF had increased putaminal [ 18 F]FDOPA uptake on PET, as in our study, suggesting neurotrophic effect on putaminal DA neurons.…”

GDNF/RET signaling pathway activation eliminates Lewy Body pathology in midbrain dopamine neurons

“…22 1 years due to inconclusive results of clinical trials with GDNF (Paul and Sullivan, 2019) and preclinical and 2 patient data suggesting the loss of RET receptor in later stages of PD (Decressac et al, 2012;Decressac 3 et al, 2013;Decressac et al, 2011). However, as discussed above, this might not be true for all 4 population of patients, especially those at earlier stages of the disease, and recent clinical trials for 5 GDNF, while not meeting clinical endpoints, demonstrated feasibility of safe, long term GDNF 6 administration (Whone et al, 2019a;Whone et al, 2019b). Importantly, discussing the modest efficacy 7 of GDNF in the latest clinical studies, the authors suggested future modifications of GDNF trials to 8 increase GDNF dosing or include patients at early stages of PD, what is strongly supported by our data.…”

Is It Possible to Conduct a Multi-Arm Multi-Stage Platform Trial in Parkinson’s Disease: Lessons Learned from Other Neurodegenerative Disorders and Cancer

“…Only 11 of 29 published phase II studies included at least one biomarker measurement in their protocol. These included 11 studies with brain imaging assessments [24,[58][59][60][61][62][63][64], one assessment of 8-hydroxy-2' -deoxyguanosine measurement in plasma and one in urine [65], as well as two studies with cerebrospinal fluid (CSF) analysis of protein aggregation [66,67]. Progress on the usefulness of imaging techniques and fluid or tissue biomarkers has been reviewed extensively by others [56,57,68].…”