Glial cell line-derived neurotrophic factor (GDNF): a drug candidate for the treatment of Parkinson’s disease

1998 ◽  
Vol 245 (S3) ◽  
pp. P35-P42 ◽  
Author(s):  
R. Grondin ◽  
Don M. Gash
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Line ◽  
Glial Cell ◽  
Neurotrophic Factor ◽  
Drug Candidate

scholarly journals The Parkinson’s Disease Comprehensive Response (PDCORE): a composite approach integrating three standard outcome measures

2020 ◽  
Vol 2 (2) ◽  
Author(s):  
Matthias Luz ◽  
Alan Whone ◽  
Niccolò Bassani ◽  
Richard K Wyse ◽  
Glenn T Stebbins ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Line ◽  
Glial Cell ◽  
Neurotrophic Factor ◽  
Rating Scale ◽  
Initial Development ◽  
Disease Rating ◽  
Recent Phase ◽  
Data Source

Abstract There is an increasing need for improved endpoints to assess clinical trial effects in Parkinson’s disease. We propose the Parkinson’s Disease Comprehensive Response as a novel weighted composite endpoint integrating changes measured in three established Parkinson’s outcomes, including: OFF state Movement Disorder Society Unified Parkinson’s Disease Rating Scale Motor Examination scores; Motor Experiences of Daily Living scores; and total good-quality ON time per day. The data source for the initial development of the composite described herein was a recent Phase II trial of glial cell line-derived neurotrophic factor. A wide range of clinically derived relative weights was assessed to normalize for differentially scoring base rates with each endpoint component. The Parkinson’s disease comprehensive response, in contrast to examining practically defined OFF state Unified Parkinson’s Disease Rating Scale Motor Examination scores alone, showed stability over 40 weeks in placebo patients, and all 432 analyses in this permutation exercise yielded significant differences in favour of glial cell line-derived neurotrophic factor. The findings were consistent with results obtained employing three different global statistical test methodologies and with patterns of intra-patient change. Based on our detailed analyses, we conclude it worth prospectively evaluating the clinical utility, validity and regulatory feasibility of using clinically supported final Parkinson’s disease comprehensive response formulas (for both the Unified Parkinson’s Disease Rating Scale-based and Movement Disorders Society-Unified Parkinson’s Disease Rating Scale-based versions) in future disease-modifying Parkinson’s trials. Whilst the data source employed in the initial development of this weighted composite score is from a recent Phase II trial of glial cell line-derived neurotrophic factor, we wish to stress that the results are not described to provide post hoc evidence of the efficacy of glial cell line-derived neurotrophic factor but rather are presented to further the debate of how current regulatory approved rating scales may be combined to address some of the recognized limitations of using individual scales in isolation.

scholarly journals Molecular targets for endogenous glial cell line-derived neurotrophic factor modulation in striatal parvalbumin interneurons

2020 ◽  
Vol 2 (2) ◽  
Author(s):  
Daniel Enterría-Morales ◽  
Natalia López-González del Rey ◽  
Javier Blesa ◽  
Ivette López-López ◽  
Sarah Gallet ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Line ◽  
Glial Cell ◽  
Neurotrophic Factor ◽  
Neuronal Degeneration ◽  
Molecular Targets ◽  
Membrane Receptors ◽  
Parvalbumin Interneurons ◽  
Parvalbumin Neurons

Abstract Administration of recombinant glial cell line-derived neurotrophic factor into the putamen has been tested in preclinical and clinical studies to evaluate its neuroprotective effects on the progressive dopaminergic neuronal degeneration that characterizes Parkinson’s disease. However, intracerebral glial cell line-derived neurotrophic factor infusion is a challenging therapeutic strategy, with numerous potential technical and medical limitations. Most of these limitations could be avoided if the production of endogenous glial cell line-derived neurotrophic factor could be increased. Glial cell line-derived neurotrophic factor is naturally produced in the striatum from where it exerts a trophic action on the nigrostriatal dopaminergic pathway. Most of striatal glial cell line-derived neurotrophic factor is synthesized by a subset of GABAergic interneurons characterized by the expression of parvalbumin. We sought to identify molecular targets specific to those neurons and which are putatively associated with glial cell line-derived neurotrophic factor synthesis. To this end, the transcriptomic differences between glial cell line-derived neurotrophic factor-positive parvalbumin neurons in the striatum and parvalbumin neurons located in the nearby cortex, which do not express glial cell line-derived neurotrophic factor, were analysed. Using mouse reporter models, we have defined the genomic signature of striatal parvalbumin interneurons obtained by fluorescence-activated cell sorting followed by microarray comparison. Short-listed genes were validated by additional histological and molecular analyses. These genes code for membrane receptors (Kit, Gpr83, Tacr1, Tacr3, Mc3r), cytosolic proteins (Pde3a, Crabp1, Rarres2, Moxd1) and a transcription factor (Lhx8). We also found the proto-oncogene cKit to be highly specific of parvalbumin interneurons in the non-human primate striatum, thus highlighting a conserved expression between species and suggesting that specific genes identified in mouse parvalbumin neurons could be putative targets in the human brain. Pharmacological stimulation of four G-protein-coupled receptors enriched in the striatal parvalbumin interneurons inhibited Gdnf expression presumably by decreasing cyclic adenosine monophosphate formation. Additional experiments with pharmacological modulators of adenylyl cyclase and protein kinase A indicated that this pathway is a relevant intracellular route to induce Gdnf gene activation. This preclinical study is an important step in the ongoing development of a specific pro-endo-glial cell line-derived neurotrophic factor pharmacological strategy to treat Parkinson’s disease.

Enhancement of survival of stored dopaminergic cells and promotion of graft survival by exposure of human fetal nigral tissue to glial cell line—derived neurotrophic factor in patients with Parkinson's disease

2000 ◽  
Vol 92 (5) ◽  
pp. 863-869 ◽  
Author(s):  
Ivar Mendez ◽  
Alain Dagher ◽  
Murray Hong ◽  
Adam Hebb ◽  
Paula Gaudet ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Line ◽  
Glial Cell ◽  
Graft Survival ◽  
Neurotrophic Factor ◽  
Storage Period ◽  
Content Type ◽  
Dopaminergic Cells ◽  
Positron Emission

✓ The authors have studied the ability of glial cell line—derived neurotrophic factor (GDNF) to promote survival of human fetal dopaminergic tissue after a storage period of 6 days and subsequent implantation into the human putamen. The results indicate that GDNF promotes survival of stored dopaminergic cells. Cells stored without GDNF had a 30.1% decrease in survival time compared with those exposed to GDNF. Two patients with Parkinson's disease received bilateral putaminal implants of fetal dopaminergic cells exposed to GDNF for 6 days and showed enhancement of graft survival as assessed by positron emission tomography scanning. A mean increase of 107% in putaminal fluorodopa uptake from baseline values was observed 12 months postgrafting.

Delayed gene therapy of glial cell line-derived neurotrophic factor is efficacious in a rat model of Parkinson's disease

2005 ◽  
Vol 134 (1) ◽  
pp. 155-161 ◽  
Author(s):  
Jie-Sheng Zheng ◽  
Ling-Ling Tang ◽  
Shu-Sen Zheng ◽  
Ren-Ya Zhan ◽  
Yong-Qing Zhou ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Gene Therapy ◽  
Parkinson's Disease ◽  
Cell Line ◽  
Glial Cell ◽  
Rat Model ◽  
Neurotrophic Factor
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