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Toxicologic Pathology
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Articles

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

David N. Hovland, Jr.1, Robert B. Boyd2, Mark T. Butt3, Jeffery A. Engelhardt1, Michael S. Moxness1, Mark H. Ma1, Maurice G. Emery1, Nadia B. Ernst1, Randall P. Reed2, Jillynne R. Zeller2, Don M. Gash4, Donna M. Masterman1, Beth M. Potter1, Mary E. Cosenza1 and Ruth M. Lightfoot1

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

Toxicologic Pathology, Vol. 35, No. 5, 676-692 (2007)
DOI: 10.1080/01926230701481899
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