Enomaa N, Danos O, Peltonen L, Jalanko A
Department of Human Molecular Genetics, National Public Health Institute, Helsinki, Finland.
Hum Gene Ther. 1995 Jun;6(6):723-31. doi: 10.1089/hum.1995.6.6-723.
The ability of lysosomal enzymes to be secreted and subsequently captured by adjacent cells provides an excellent basis for investigating different therapy strategies in lysosomal storage disorders. Aspartylglucosaminuria (AGU) is caused by deficiency of aspartylglucosaminidase (AGA) leading to interruption of the ordered breakdown of glycoproteins in lysosomes. As a consequence of the disturbed glycoprotein catabolism, patients with AGU exhibit severe cell dysfunction especially in the central nervous system (CNS). The uniform phenotype observed in these patients will make effective evaluation of treatment trials feasible in future. Here we have used fibroblasts and lymphoblasts from AGU patients and murine neural cell lines as targets to evaluate in vitro the feasibility of enzyme replacement and gene therapy in the treatment of this disorder. Complete correction of the enzyme deficiency was obtained both with recombinant AGA enzyme purified from CHO-K1 cells and with retrovirus-mediated transfer of the AGA gene. Furthermore, we were able to demonstrate enzyme correction by cell-to-cell interaction of transduced and nontransduced cells.
溶酶体酶分泌并随后被相邻细胞捕获的能力为研究溶酶体贮积症的不同治疗策略提供了良好的基础。天冬氨酰葡糖胺尿症（AGU）是由天冬氨酰葡糖胺酶（AGA）缺乏引起的，导致溶酶体中糖蛋白有序分解的中断。由于糖蛋白分解代谢紊乱，AGU患者表现出严重的细胞功能障碍，尤其是在中枢神经系统（CNS）。在这些患者中观察到的统一表型将使未来对治疗试验的有效评估成为可能。在这里，我们以AGU患者的成纤维细胞和淋巴细胞以及小鼠神经细胞系为靶点，在体外评估酶替代疗法和基因疗法治疗这种疾病的可行性。从CHO-K1细胞中纯化的重组AGA酶和逆转录病毒介导的AGA基因转移都能完全纠正酶缺乏。此外，我们能够通过转导细胞和未转导细胞之间的细胞间相互作用证明酶的纠正。
