Clearance and toxicity of recombinant methionyl human glial cell line-derived neurotrophic factor (r-metHu GDNF) following acute convection-enhanced delivery into the striatum

• Published in: PloS one Vol. 8; no. 3; p. e56186
• Main Authors: Taylor, Hannah, Barua, Neil, Bienemann, Alison, Wyatt, Marcella, Castrique, Emma, Foster, Rebecca, Luz, Matthias, Fibiger, Christian, Mohr, Erich, Gill, Steven
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 20.03.2013; Public Library of Science (PLoS)
• Subjects: Accumulation; Adapters; Analysis; Animals; Axonogenesis; Binding sites; Biology; Calcium; Care and treatment; Cell Death - drug effects; Cerebrospinal fluid; Clinical trials; Convection; Corpus Striatum - drug effects; Corpus Striatum - metabolism; Corpus Striatum - pathology; Dosage; Drug dosages; Enzyme-linked immunosorbent assay; Glia; Glial cell line-derived neurotrophic factor; Glial Cell Line-Derived Neurotrophic Factor - administration & dosage; Glial Cell Line-Derived Neurotrophic Factor - pharmacokinetics; Glial Cell Line-Derived Neurotrophic Factor - toxicity; Glial fibrillary acidic protein; Gliosis; Humans; Immunohistochemistry; Infusion; Infusion Pumps; Low concentrations; Male; Medical imaging; Medical research; Medical treatment; Medicine; Metabolic Clearance Rate; Microglia; Movement disorders; mRNA; Neostriatum; Neurodegenerative diseases; Neurogenesis - drug effects; Neuroglia - metabolism; Neuronal-glial interactions; Neurosurgery; Neurotoxicity; Parkinson disease; Parkinson Disease - drug therapy; Parkinson Disease - metabolism; Parkinson's disease; Parkinsons disease; Putamen; Rats; Rats, Wistar; Recombinant Proteins - administration & dosage; Recombinant Proteins - pharmacokinetics; Recombinant Proteins - toxicity; Risk factors; Rodents; Studies; Synaptogenesis; Synaptophysin; Tissue Distribution; Toxicity; Translation; United Kingdom > UK; British Columbia Canada; Canada
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0056186

Despite promising early results, clinical trials involving the continuous delivery of recombinant methionyl human glial cell line-derived neurotrophic factor (r-metHuGDNF) into the putamen for the treatment of Parkinson's disease have shown evidence of poor distribution and toxicity due to point-source accumulation. Convection-enhanced delivery (CED) has the potential to facilitate more widespread and clinically effective drug distribution. We investigated acute CED of r-metHuGDNF into the striatum of normal rats in order to assess tissue clearance, toxicity (neuron loss, gliosis, microglial activation, and decreases in synaptophysin), synaptogenesis and neurite-outgrowth. We investigated a range of clinically relevant infused concentrations (0.1, 0.2, 0.6 and 1.0 µg/µL) and time points (2 and 4 weeks) in order to rationalise a dosing regimen suitable for clinical translation. Two weeks after single dose CED, r-metHuGDNF was below the limit of detection by ELISA but detectable by immunohistochemistry when infused at low concentrations (0.1 and 0.2 µg/µL). At these concentrations, there was no associated neuronal loss (neuronal nuclei, NeuN, immunohistochemistry) or synaptic toxicity (synaptophysin ELISA). CED at an infused concentration of 0.2 µg/µL was associated with a significant increase in synaptogenesis (p<0.01). In contrast, high concentrations of r-metHuGDNF (above 0.6 µg/µL) were associated with neuronal and synaptic toxicity (p<0.01). Markers for gliosis (glial fibrillary acidic protein, GFAP) and microglia (ionized calcium-binding adapter molecule 1, Iba1) were restricted to the needle track and the presence of microglia had diminished by 4 weeks post-infusion. No change in neurite outgrowth (Growth associated protein 43, GAP43, mRNA) compared to artificial cerebral spinal fluid (aCSF) control was observed with any infused concentration. The results of this study suggest that acute CED of low concentrations of GDNF, with dosing intervals determined by tissue clearance, has most potential for effective clinical translation by optimising distribution and minimising the risk of toxic accumulation.