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Reprint: Six-Month Continuous Intraputamenal Infusion Toxicity Study of Recombinant Methionyl Human Glial Cell Line-Derived Neurotrophic Factor (r-metHuGDNF) in Rhesus Monkeys

¹ Amgen Inc., Thousand Oaks, California 91320
² Northern Biomedical Research, Inc., Muskegon, Michigan 49441
³ Pathology Associates, Charles River Laboratories, Frederick, Maryland 21701
⁴ Anatomy and Neurobiology, University of Kentucky, Lexington, Kentucky 40536

Correspondence: Address correspondence to: David N. Hovland, Jr., Ph.D., Amgen, Inc., 1 Amgen Center Drive, MS 38-4-C, Thousand Oaks, CA 91320-1799; e-mail:dhovland{at}amgen.com

Recombinant human glial cell line-derived neurotrophic factor (r-metHuGDNF) is a potent neuronal growth and survival factor that has been considered for clinical use in the treatment of Parkinson’s disease (PD). Here we present results of a 6-month toxicology study in rhesus monkeys conducted to support clinical evaluation of chronic intraputamenal infusion of r-metHuGDNF for PD. Monkeys (6–9/sex/group) were treated with 0 (vehicle), 15, 30, or 100 µg/day r-metHuGDNF by continuous unilateral intraputamenal infusion (150 µl/day flow rate) for 6 months; a subset of animals (2–3/sex/group) underwent a subsequent 3-month treatment-free recovery period. Notable observations included reduced food consumption and body weight at 100 µg/day and meningeal thickening underlying the medulla oblongata and/or overlying various spinal cord segments at 30 and 100 µg/day. In addition, multifocal cerebellar Purkinje cell loss (with associated atrophy of the molecular layer and, in some cases, granule cell loss) was observed in 4 monkeys in the 100-µg/day group. This cerebellar finding has not been observed in previous nonclinical studies evaluating r-metHuGDNF. The small number of affected animals precludes definitive conclusions regarding the pathogenesis of the cerebellar lesion, but the data support an association with r-metHuGDNF treatment.

Key Words: GDNF • Parkinson’s disease • toxicology • toxicity • cerebellum • Purkinje cell • monkey • infusion • putamen • rhesus

Abbreviations: ANOVA, analysis of variance • ATP, adenosine triphosphate • BQL, below the quantification limit • CBS, citrate-buffered saline • CFR, Code of Federal Regulations • CNS, central nervous system • CSF, cerebrospinal fluid • DIC, disseminated intravascular coagulation • ECF, extracellular fluid • EPO, erythropoietin • FSE, fast spin echo • GDNF, glial cell line-derived neurotrophic factor • GFAP, glial fibrillary acidic protein • GMA, glycol methacrylate • H&E, hematoxylin and eosin • ICV, intracerebroventricular • IPu, intraputamenal • LFB-PAS, Luxol fast blue-periodic acidic Schiff • LLOQ, lower limit of quantification • mIL-3, murine interleukin-3 • MPTP, 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine • MRI, magnetic resonance imaging • PD, Parkinson’s disease • PET, positron emission tomography • RLU, relative light units • r-metHuGDNF, recombinant methionyl human GDNF • SPR, surface plasmon resonance • 6-OHDA, 6-hydroxydopamine

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