Hovland David N, Boyd Robert B, Butt Mark T, Engelhardt Jeffery A, Moxness Michael S, Ma Mark H, Emery Maurice G, Ernst Nadia B, Reed Randall P, Zeller Jillynne R, Gash Don M, Masterman Donna M, Potter Beth M, Cosenza Mary E, Lightfoot Ruth M
Amgen Inc., Thousand Oaks, CA 91320, USA.
Toxicol Pathol. 2007 Dec;35(7):1013-29. doi: 10.1177/01926230701481899.
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 microg/day r-metHuGDNF by continuous unilateral intraputamenal infusion (150 microl/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 microg/day and meningeal thickening underlying the medulla oblongata and/or overlying various spinal cord segments at 30 and 100 microg/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-microg/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.
重组人胶质细胞源性神经营养因子（r-metHuGDNF）是一种强效的神经元生长和存活因子，已被考虑用于帕金森病（PD）治疗的临床应用。在此，我们展示了一项在恒河猴身上进行的为期6个月的毒理学研究结果，以支持对r-metHuGDNF慢性脑内壳核输注治疗PD进行临床评估。将猴子（每组6 - 9只/性别）通过连续单侧脑内壳核输注（流速150微升/天），分别给予0（赋形剂）、15、30或100微克/天的r-metHuGDNF，持续6个月；一部分动物（每组2 - 3只/性别）随后经历3个月的无治疗恢复期。值得注意的观察结果包括，每天给予100微克时食物消耗和体重下降，以及每天给予30和100微克时延髓下方和/或多个脊髓节段上方的脑膜增厚。此外，在每天给予100微克组的4只猴子中观察到多灶性小脑浦肯野细胞丢失（伴有分子层相关萎缩，在某些情况下还有颗粒细胞丢失）。在之前评估r-metHuGDNF的非临床研究中未观察到这种小脑病变。受影响动物数量较少，无法就小脑病变的发病机制得出明确结论，但这些数据支持其与r-metHuGDNF治疗有关。
