Objective: Assesing the neurorestorative effect of GDNF. 

Background: GDNF is a potent neurotrophic factor. A previous placebo-controlled trial, however, at 6 months, failed to demonstrate clinical benefit, with a modest focal increase in posterior putamen ¹⁸F-DOPA uptake, in the region of the catheter tip.¹ In this prior study, GDNF was administered via abdominal-pumps delivering continuous putamenal infusions. Problematically, low-flow-rate continuous infusions can only provide diffusion dependent, non-homogeneous, spatially-restricted distribution. Hence, we have conducted an investigation, where GDNF has been administered in a novel manner, to afford convection enhanced delivery (CED), rather than diffusion dependent administration. The employed method utilized a skull mounted port permitting monthly intermittent delivery at a flow rate potentially sufficient to convect GDNF throughout the putamen. 

Methods: A single centre, 9 month, placebo-controlled, randomized, double-blind, trial where 41 Parkinson’s subjects (6, pilot phase, 35 primary phase) received 4 weekly intraputamenal infusions.  A 9 month open label extension study, where all subjects receive GDNF, is in-progress. 

Results: The primary outcome at week 40, mean percent change in motor UPDRS OFF, was negative. In the ITT Overall Population: mean percentage improvements (GDNF vs. placebo) were 20.5±18.6% vs.  12.7±15.2 (p=0.13);  a post-hoc responder analysis testing for absolute improvement ≥5 points or ≥10 points in Motor UPDRS OFF showed no difference between GDNF vs. placebo at ≥5 points but a significant difference in favour of GDNF at ≥10 points (9 [43%] vs. 0; p=0.0008).  ¹⁸F-dopa PET imaging showed no change in controls but significant increased uptake at 9 months in the GDNF group, bilaterally, in the posterior, middle and anterior putamen, where the increase in the posterior putamen was 100% (p<0.0001).  

Conclusions: We have conducted the first randomized trial in Parkinson’s, employing CED, to administer GDNF on a monthly basis, via a skull mounted port. We have shown that attending for monthly GDNF infusions is feasible, tolerable and safe. As evidenced by increased ¹⁸F-dopa PET signal, we have demonstrated delivery of GDNF sufficient to produce a biological effect across the entire putamen. After 9 months we did not meet our primary end-point but an extension study is in progress and further clinical outcomes will be presented.

References: 1: Lang AE, Gill S, Patel NK, Lozano A, Nutt JG, Penn R, Brooks DJ, Hotton G, Moro E, Heywood P, Brodsky MA, Burchiel K, Kelly P, Dalvi A, Scott B, Stacy M,Turner D, Wooten VG, Elias WJ, Laws ER, Dhawan V, Stoessl AJ, Matcham J, Coffey RJ, Traub M. Randomized controlled trial of intraputamenal glial cell line-derived neurotrophic factor infusion in Parkinson disease. Ann Neurol. 2006 Mar;59(3):459-66.

« Back to 2017 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/randomized-parkinsons-trial-of-gdnf-administered-via-intermittent-intraputamenal-convection-enhanced-delivery/