Abstract
BackgroundDespite 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.AimsWe 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.ResultsTwo 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.ConclusionThe 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.
Highlights
Parkinson’s Disease (PD) is characterised by impairment of motor function largely caused by the loss of dopaminergic neurons in the substantia nigra
Two weeks after single dose Convection-enhanced delivery (CED), r-metHuGDNF was below the limit of detection by enzyme-linked immuno-sorbent assay (ELISA) but detectable by immunohistochemistry when infused at low concentrations (0.1 and 0.2 mg/mL)
Markers for gliosis and microglia were restricted to the needle track and the presence of microglia had diminished by 4 weeks post-infusion
Summary
Parkinson’s Disease (PD) is characterised by impairment of motor function largely caused by the loss of dopaminergic neurons in the substantia nigra. Following the success of these pre-clinical studies, our research group undertook the first open-label study of continuous intraputaminal delivery of recombinant methionyl human glial cell line-derived neurotrophic factor (r-metHuGDNF) via stereotactically-placed microcatheters attached to a subcutaneous infusion pump [11]. One patient receiving unilateral infusion of r-metHuGDNF died of causes unrelated to the study, and post mortem examination confirmed that infusion of rmetHuGDNF resulted in a marked increase in tyrosine hydroxylase-positive nerve fibres, and possibly neuronal sprouting in the substantia nigra [12]. 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
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
