title: Six-month continuous intraputamenal infusion toxicity study of recombinant methionyl human glial cell line-derived neurotrophic factor (r-metHuGDNF) in rhesus monkeys.
abstract: 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 micro g/day r-metHuGDNF by continuous unilateral intraputamenal infusion (150 micro l/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 micro g/day and meningeal thickening underlying the medulla oblongata and/or overlying various spinal cord segments at 30 and 100 micro g/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-micro g/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.
authors.affiliation: Amgen Inc., Thousand Oaks, California 91320, USA. dhovland@amgen.com
authors.forename: David N
authors.initials: DN
authors.lastname: Hovland
authors.forename: Robert B
authors.initials: RB
authors.lastname: Boyd
authors.forename: Mark T
authors.initials: MT
authors.lastname: Butt
authors.forename: Jeffery A
authors.initials: JA
authors.lastname: Engelhardt
authors.forename: Michael S
authors.initials: MS
authors.lastname: Moxness
authors.forename: Mark H
authors.initials: MH
authors.lastname: Ma
authors.forename: Maurice G
authors.initials: MG
authors.lastname: Emery
authors.forename: Nadia B
authors.initials: NB
authors.lastname: Ernst
authors.forename: Randall P
authors.initials: RP
authors.lastname: Reed
authors.forename: Jillynne R
authors.initials: JR
authors.lastname: Zeller
authors.forename: Don M
authors.initials: DM
authors.lastname: Gash
authors.forename: Donna M
authors.initials: DM
authors.lastname: Masterman
authors.forename: Beth M
authors.initials: BM
authors.lastname: Potter
authors.forename: Mary E
authors.initials: ME
authors.lastname: Cosenza
authors.forename: Ruth M
authors.initials: RM
authors.lastname: Lightfoot
mesh_terms: D000818:Animals; D000906:Antibodies / Q000032:analysis; D002531:Cerebellum / Q000187:drug effects / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000032:analysis / Q000276:immunology / Q000493:pharmacokinetics / Q000633:toxicity*; D007150:Immunohistochemistry; D008253:Macaca mulatta; D008279:Magnetic Resonance Imaging; D008297:Male; D008578:Meninges / Q000187:drug effects / Q000473:pathology; D011699:Putamen / Q000187:drug effects*; D011994:Recombinant Proteins / Q000633:toxicity
chemical_list: D000906:Antibodies; D051100:Glial Cell Line-Derived Neurotrophic Factor; D011994:Recombinant Proteins