Whone A, Luz M, Boca M, et al. Randomized trial of intermittent intraputamenal glial cell line‐derived neurotrophic factor in Parkinson's disease. Brain 2019;142:512–525.
Treatments that halt or reverse nigrostriatal neurodegeneration in Parkinson's disease (PD) are yet to arrive and represent an unmet need. Glial cell line–derived neurotrophic factor (GDNF) may emerge as a novel therapy for PD.1 In animal models, GDNF has shown to promote differentiation and survival of midbrain dopaminergic neurons and increase dopamine uptake.2, 3
Previously, the clinical benefit of putamenal GDNF administration in PD was not demonstrated.4 Development of an accurate and practical delivery route for GDNF into affected areas has presented a major challenge. This, in part, motivated the approach by Whone et al., using an innovative method of administration, convection‐enhanced delivery (CED), to achieve widespread, homogeneous, and bilateral GDNF distribution in the putamina.5 In a single‐center, placebo‐controlled, randomized, and double‐blind trial, the researchers tested the hypothesis that intermittent bilateral intraputamenal infusions of GDNF produces clinical benefit in patients with PD.
Preceded by a pilot stage with 6 patients, 35 patients were randomized (1:1) to drug or placebo (artificial cerebrospinal fluid [CSF]), undergoing 10 treatments at 4‐week intervals. Additionally, all patients underwent 18F‐DOPA PET scanning at baseline and 2 weeks after the last infusion. The primary endpoint was percentage change from baseline in the OFF state UPDRS motor score after 40 weeks. Secondary endpoints included percentage change from baseline to week 40 in the UPDRS motor score in the ON state, total score, and change in the patients' PD diary ratings as well as the change in 18F‐DOPA uptake.
No significant differences in clinical primary and secondary outcomes were detected between baseline and week 40. However, in the GDNF group, 18F‐DOPA uptake rate in the putamen increased significantly between baseline and week 40.
The researchers showed CED to be safe and reliable. GDNF was well tolerated (although serious adverse events were reported in 5 patients in the GDNF group—3 were device related, 2 were hypertrophic skin reactions, and 1 a possible infection). Failure to detect differences in the clinical primary or secondary endpoints may have reflected the brief study duration and reduction in tissue GDNF concentrations, attributed to a larger volume of putaminal distribution and intermittent rather than continuous dosing. Furthermore, inadequate washout of dopaminergic drugs may not have been achieved, thus masking any GDNF effects. The researchers also made note of a larger‐than‐expected placebo effect that may also have confounded the results.
The magnitude of improvement in 18F‐DOPA uptake rate throughout the putamen was akin to a shift from moderate‐to‐advanced PD to mild PD, though once again, the lack of clinical correlates merits further attention and the scan technique did not allow for precise measurement from nigral dopaminergic neurons.
The encouraging findings of this study may hint at neuroprotection and thus warrant further, more long‐term study of GDNF, perhaps with a wider scope of clinical outcomes and more precise radiotracers. This trial also paves the way for future treatment targets and new neurotrophic factors to mitigate neurodegeneration in PD.
Author Roles
(1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the First Draft, B. Review and Critique.
N.C.: 1A, 1B, 1C, 3A, 3B
A.M.: 1A, 1B, 1C, 3A, 3B
V.B.: 1A, 1B, 1C, 3A, 3B
Disclosures
Ethical Compliance Statement
We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. The authors confirm that the approval of an institutional review board was not required for this work based on the submission type.
Funding Sources and Conflicts of Interest
The authors report no sources of funding and no conflicts of interest.
Financial Disclosures for previous 12 months
The authors declare that there are no disclosures to report.
Relevant disclosures and conflicts of interest are listed at the end of this article.
References
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