Comparative Studies of Continuous Versus Pulsatile Delivery of a Novel Mammalian Cell-Derived Variant of GDNF (GDNFv) into the Rhesus Macaque Striatum
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Abstract
Glial cell line-derived neurotrophic factor (GDNF) remains a promising disease modifying therapeutic agent for the dopamine-containing neurons that are affected in Parkinson’s disease and recent clinical findings show renewed promise for its use in patients with Parkinson’s disease. However, translating this approach from research laboratories to the clinic has been met with obstacles, including insufficient brain biodistribution, immunogenicity, and poor stability of unglycosylated wildtype GDNF produced from bacteria. We have previously reported that continuous infusion of a novel glycosylated mammalian variant of GDNF (GDNFv) has increased biodistribution compared to wildtype GDNF along with increased dopamine turnover in the non-human primate brain. Here, we extend these findings by comparing continuous versus pulsatile intrastriatal infusion of GDNFv in intact rhesus macaques. Intermittent, pulsatile delivery paradigms were explored to possibly enhance drug distribution in the brain while decreasing the total amount of drug and infusion volume needed to achieve target activation. Vehicle or GDNFv was directly administered into the putamen via a pump and catheter system using a constant flow rate or using pulsatile profiles of two patterns: pulsatile infusion of 24-hour duration or 48-hour duration. Study endpoints involved comparisons of brain biodistribution, retrograde transport to nigral neurons and dopamine turnover. Each catheter was placed in or near the center of the putamen as confirmed by post-operative magnetic resonance imaging. Our results support that continuous and pulsatile administration of GDNFv was well tolerated in all animals. In addition, pulsatile delivery of GDNFv demonstrated favorable physiological activity of potential therapeutic value with biodistribution, retrograde transport to nigral cells and significant dopamine turnover modulation comparable or better than that achieved with continuous flow delivery. More importantly, the animals administered GDNFv via pulsatile protocols only received half the total drug amount and half the infused volume used in the continuously-infused animals, while still attaining a similar efficacy in increasing dopamine turnover. These data suggest that pulsatile delivery of trophic factors, such as GDNFv, may be a viable disease altering strategy for patients with Parkinson’s disease by offering a means to reduce the drug amount needed to improve dopamine function while limiting potential therapeutic barriers.
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