Six-month continuous intraputamenal infusion toxicity study of recombinant methionyl human glial cell line-derived neurotrophic factor (r-metHuGDNF) in rhesus monkeys.
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.
Hovland
David N
DN
Amgen Inc., Thousand Oaks, California 91320, USA. dhovland@amgen.com
Boyd
Robert B
RB
Butt
Mark T
MT
Engelhardt
Jeffery A
JA
Moxness
Michael S
MS
Ma
Mark H
MH
Emery
Maurice G
MG
Ernst
Nadia B
NB
Reed
Randall P
RP
Zeller
Jillynne R
JR
Gash
Don M
DM
Masterman
Donna M
DM
Potter
Beth M
BM
Cosenza
Mary E
ME
Lightfoot
Ruth M
RM
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
D000906:Antibodies; D051100:Glial Cell Line-Derived Neurotrophic Factor; D011994:Recombinant Proteins