Randomized trial of intermittent intraputamenal glial cell line-derived neurotrophic factor in Parkinson’s disease
Open accessAbstract
We investigated the effects of glial cell line-derived neurotrophic factor (GDNF) in Parkinson's disease, using intermittent intraputamenal convection-enhanced delivery via a skull-mounted transcutaneous port as a novel administration paradigm to potentially afford putamen-wide therapeutic delivery. This was a single-centre, randomized, double-blind, placebo-controlled trial. Patients were 35-75 years old, had motor symptoms for 5 or more years, and presented with moderate disease severity in the OFF state [Hoehn and Yahr stage 2-3 and Unified Parkinson's Disease Rating Scale motor score (part III) (UPDRS-III) between 25 and 45] and motor fluctuations. Drug delivery devices were implanted and putamenal volume coverage was required to exceed a predefined threshold at a test infusion prior to randomization. Six pilot stage patients (randomization 2:1) and 35 primary stage patients (randomization 1:1) received bilateral intraputamenal infusions of GDNF (120 µg per putamen) or placebo every 4 weeks for 40 weeks. Efficacy analyses were based on the intention-to-treat principle and included all patients randomized. The primary outcome was the percentage change from baseline to Week 40 in the OFF state (UPDRS-III). The primary analysis was limited to primary stage patients, while further analyses included all patients from both study stages. The mean OFF state UPDRS motor score decreased by 17.3 ± 17.6% in the active group and 11.8 ± 15.8% in the placebo group (least squares mean difference: -4.9%, 95% CI: -16.9, 7.1, P = 0.41). Secondary endpoints did not show significant differences between the groups either. A post hoc analysis found nine (43%) patients in the active group but no placebo patients with a large clinically important motor improvement (≥10 points) in the OFF state (P = 0.0008). 18F-DOPA PET imaging demonstrated a significantly increased uptake throughout the putamen only in the active group, ranging from 25% (left anterior putamen; P = 0.0009) to 100% (both posterior putamina; P < 0.0001). GDNF appeared to be well tolerated and safe, and no drug-related serious adverse events were reported. The study did not meet its primary endpoint. 18F-DOPA imaging, however, suggested that intermittent convection-enhanced delivery of GDNF produced a putamen-wide tissue engagement effect, overcoming prior delivery limitations. Potential reasons for not proving clinical benefit at 40 weeks are discussed.
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Clinical trials using neurotrophins in the treatment of Parkinson's disease are rather limited to GDNF administration instead of BDNF.
“Clinical trials using NTs in the treatment of PD are rather limited to GDNF administration instead of BDNF.”
From BDNF as a Promising Therapeutic Agent in Parkinson’s Disease (2020) · cites this paper as [110]
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- Authors
- Whone, A., Luz, M., Boca, M., Woolley, M., Mooney, L., Dharia, S., Broadfoot, J., Cronin, D., Schroers, C., Barua, N. U., Longpre, L., Barclay, C. L., Boiko, C., Johnson, G. A., Fibiger, H. C., Harrison, R., Lewis, O., Pritchard, G., Howell, M., Irving, C., Johnson, D., Kinch, S., Marshall, C., Lawrence, A. D., Blinder, S., Sossi, V., Stoessl, A. J., Skinner, P., Mohr, E., & Gill, S. S.
- Affiliations
- North Bristol NHS Trust (GB)
- MedGenesis Therapeutix (Canada) (CA)
- Neurological and Musculoskeletal Sciences Division, North Bristol NHS Trust, Bristol, UK
- Renishaw (United Kingdom) (GB)
- Cardiff University (GB)
- University of British Columbia (CA)
- Corresponding author
- Gill, Steven S
- ORCID
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2019-02-26
- Volume
- 142
- Issue
- 3
- Pages
- 512-525
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- PMC
- PMC6391602
- OpenAlex
- W2916149712
- Cited by
- 282
- References
- 51
- Citations by year
- 2026: 20 · 2025: 35 · 2024: 25 · 2023: 24 · 2022: 29 · 2021: 53 · 2020: 65 · 2019: 30 · 2013: 1
- FWCI
- 29.66
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Brain (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Explore Bristol Research (publishedVersion, cc-by)
- ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
- Funders
- Parkinson’s UK (J-1102)
- Cure Parkinson’s
- North Bristol NHS Trust
- MedGenesis Therapeutix
- The Gatsby Foundation
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Neurology › Neurological disorders and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Keywords
- glial cell line-derived neurotrophic factor, Parkinson's disease, convection-enhanced delivery, motor fluctuations, 18F-DOPA PET, putamen, neuroprotection
- MeSH terms
- Adult, Aged, Double-Blind Method, Female, Humans, Male, Middle Aged, Neuroglia, Parkinson Disease, Infusion Pumps, Implantable, Placebo Effect, Treatment Outcome, Glial Cell Line-Derived Neurotrophic Factor
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