Intermittent convection-enhanced delivery of GDNF into rhesus monkey putamen: absence of local or cerebellar toxicity

Abstract

Glial cell line-derived neurotrophic factor (GDNF) has demonstrated neurorestorative and neuroprotective effects in rodent and nonhuman primate models of Parkinson’s disease. However, continuous intraputamenal infusion of GDNF (100 µg/day) resulted in multifocal cerebellar Purkinje cell loss in a 6-month toxicity study in rhesus monkeys. It was hypothesized that continuous leakage of GDNF into the cerebrospinal fluid compartment during the infusions led to down-regulation of GDNF receptors on Purkinje cells, and that subsequent acute withdrawal of GDNF then mediated the observed cerebellar lesions. Here we present the results of a 9-month toxicity study in which rhesus monkeys received intermittent intraputamenal infusions via convection-enhanced delivery. Animals were treated with GDNF (87.1 µg; N = 14) or vehicle (N = 6) once every 4 weeks for a total of 40 weeks (11 treatments). Four of the GDNF-treated animals were utilized in a satellite study assessing the impact of concomitant catheter repositioning prior to treatment. In the main study, eight animals (5 GDNF, 3 control) were euthanized at the end of the treatment period, along with the four satellite study animals, while the remaining eight animals (5 GDNF, 3 control) were euthanized at the end of a 12-week recovery period. There were no GDNF-related adverse effects and in particular, no GDNF-related microscopic findings in the brain, spinal cord, dorsal root ganglia, or trigeminal ganglia. Therefore, 87.1 µg/4 weeks is considered the no observed adverse effect level for GDNF in rhesus monkeys receiving intermittent, convection-enhanced delivery of GDNF for 9 months.Electronic supplementary materialThe online version of this article (10.1007/s00204-018-2222-z) contains supplementary material, which is available to authorized users.

Randomized trial of intermittent intraputamenal glial cell line-derived neurotrophic factor in Parkinson’s disease

“…However, the latter concentration is very close to the concentration used in the rhesus monkeys that developed cerebellar lesions (0.67 µg/µl), and was therefore considered too high at the time (Hovland et al , 2007). Meanwhile, a further 9-month toxicity study testing the intermittent dosing paradigm in rhesus monkeys has established 0.67 µg/µl as the no-observed-adverse-effect level (Luz et al , 2018), thus opening the door to include this threefold higher dose level in future clinical studies.…”

Extended Treatment with Glial Cell Line-Derived Neurotrophic Factor in Parkinson’s Disease

“…Using a higher dose with intermittent administration, however, would have required a higher infusate GDNF concentration (e.g., 0.6 g/L) which could not be implemented before addressing concerns about unexpected cerebellar toxicity in rhesus monkeys that had been treated with a similar concentration, albeit in a continuous dosing study and at a total dose well beyond the clinical range [22]. In the meantime, the safety of the higher concentration, when used intermittently, has been confirmed [23], thus enabling its clinical use in the future.…”

Deformational changes after convection-enhanced delivery in the pediatric brainstem

“…The return toward baseline in brainstem volume does support the feasibility to use serial, repeat infusions. 9,12,15 However, multiple factors will play a role in the safety of repeat infusions, and the timeline for these repeat infusions remains unclear. The relationship we detailed between infusion volume and pontine/ventricular changes suggests a need for caution with continuous large-volume infusions within the brainstem.…”