Department of Chemistry, University of Toledo, Toledo, OH 43606, USA.
Mol Genet Metab. 2011 Feb;102(2):176-80. doi: 10.1016/j.ymgme.2010.10.012. Epub 2010 Oct 30.
Canavan disease is a fatal neurological disease without any effective treatments to slow the relentless progress of this disorder. Enzyme replacement therapy has been used effectively to treat a number of metabolic disorders, but the presence of the blood-brain-barrier presents an additional challenge in the treatment of neurological disorders. Studies have begun with the aim of establishing a treatment protocol that can effectively replace the defective enzyme in Canavan disease patients. The human enzyme, aspartoacylase, has been cloned, expressed and purified, and the surface lysyl groups modified through PEGylation. Fully active modified enzymes were administered to mice that are defective in this enzyme and that show many of the symptoms of Canavan disease. Statistically significant increases in brain enzyme activity levels have been achieved in this animal model, as well as decreases in the elevated substrate levels that mimic those found in Canavan disease patients. These results demonstrate that the modified enzyme is gaining access to the brain and functions to correct this metabolic defect. The stage is now set for a long term study to optimize this enzyme replacement approach for the development of a treatment protocol.
Canavan 病是一种致命的神经退行性疾病，目前尚无任何有效治疗方法能够减缓这种疾病的进展。酶替代疗法已被有效地用于治疗多种代谢紊乱，但血脑屏障的存在给治疗神经退行性疾病带来了额外的挑战。研究已经开始，旨在建立一种治疗方案，能够有效地替代 Canavan 病患者中缺陷的酶。已经克隆、表达和纯化了人类酶天门冬氨酸酰基酶，并通过 PEGylation 修饰了表面赖氨酸基团。经过修饰的完全活性酶已被施用于缺乏这种酶且表现出许多 Canavan 病症状的小鼠。在这种动物模型中，脑酶活性水平显著升高，同时升高的底物水平也降低，与 Canavan 病患者中的水平相似。这些结果表明，修饰后的酶能够进入大脑并发挥作用，纠正这种代谢缺陷。现在已经为一项长期研究做好了准备，以优化这种酶替代方法，制定治疗方案。
