Hemsley Kim M, King Barbara, Hopwood John J
Lysosomal Diseases Research Unit, Department of Genetic Medicine, Children, Youth and Women's Health Service, Adelaide 5006, Australia.
Mol Genet Metab. 2007 Mar;90(3):313-28. doi: 10.1016/j.ymgme.2006.10.005. Epub 2006 Dec 12.
At present, there is no widely available, safe and effective treatment for lysosomal storage disorders (LSD) that affect the brain. We have used a naturally occurring mouse model of mucopolysaccharidosis type IIIA (MPS IIIA) or Sanfilippo syndrome, to evaluate the effect of repeated injection of recombinant human sulfamidase (rhSGSH) into the cerebrospinal fluid via the cisterna magna (CM) on central nervous system (CNS) pathology and behavioral function. Mice received up to seven injections of rhSGSH (5-20 microg rhSGSH per injection) or vehicle on a fortnightly or monthly basis. A dose-dependent reduction in the level of a heparan sulfate-derived monosulfated disaccharide was observed within the brain (up to 62% reduction compared with vehicle-treated MPS IIIA mice) and spinal cord (up to 71% reduction). Ultrastructural examination revealed a reduction in lysosomal vesicle formation in various cell types and fewer (ubiquitin-positive) axonal spheroids were observed in several brain regions. The biochemical changes were accompanied by improved behavior, particularly in mice-treated more frequently. A humoral immune response to rhSGSH was observed in treated animals. Intra-CM injection of lysosomal enzyme may therefore represent an immediately applicable method of treating the CNS effects of this and potentially other LSD that affect the brain.
目前，对于影响大脑的溶酶体贮积症（LSD），尚无广泛可用、安全有效的治疗方法。我们使用了III型黏多糖贮积症（MPS IIIA）或桑菲利波综合征的天然小鼠模型，来评估通过枕大池（CM）向脑脊液中反复注射重组人硫酸酰胺酶（rhSGSH）对中枢神经系统（CNS）病理和行为功能的影响。小鼠每隔两周或每月接受多达七次rhSGSH注射（每次注射5 - 20微克rhSGSH）或赋形剂注射。在脑内（与接受赋形剂治疗的MPS IIIA小鼠相比，减少高达62%）和脊髓中（减少高达71%）观察到硫酸乙酰肝素衍生的单硫酸化二糖水平呈剂量依赖性降低。超微结构检查显示，各种细胞类型中溶酶体囊泡形成减少，并且在几个脑区观察到较少的（泛素阳性）轴突球状体。生化变化伴随着行为改善，尤其是在接受更频繁治疗的小鼠中。在接受治疗的动物中观察到对rhSGSH的体液免疫反应。因此，通过CM注射溶酶体酶可能是一种可立即应用于治疗这种以及可能影响大脑的其他LSD对CNS影响的方法。
