Bourgoin C, Emiliani C, Kremer E J, Gelot A, Tancini B, Gravel R A, Drugan C, Orlacchio A, Poenaru L, Caillaud C
Laboratoire de Génétique, Département Génétique, Développement et Pathologie Moléculaire, Institut Cochin, INSERM, CNRS, Paris V University, Paris, France.
Gene Ther. 2003 Oct;10(21):1841-9. doi: 10.1038/sj.gt.3302081.
Sandhoff disease is a severe inherited neurodegenerative disorder resulting from deficiency of the beta-subunit of hexosaminidases A and B, lysosomal hydrolases involved in the degradation of G(M2) ganglioside and related metabolites. Currently, there is no viable treatment for the disease. Here, we show that adenovirus-mediated transfer of the beta-subunit of beta-hexosaminidase restored Hex A and Hex B activity after infection of Sandhoff fibroblasts. Gene transfer following intracerebral injection in a murine model of Sandhoff disease resulted in near-normal level of enzymatic activity in the entire brain at the different doses tested. The addition of hyperosmotic concentrations of mannitol to the adenoviral vector resulted in an enhancement of vector diffusion in the injected hemisphere. Adenoviral-induced lesions were found in brains injected with a high dose of the vector, but were not detected in brains injected with 100-fold lower doses, even in the presence of mannitol. Our data underline the advantage of the adjunction of mannitol to low doses of the adenoviral vector, allowing a high and diffuse transduction efficiency without viral cytotoxicity.
桑德霍夫病是一种严重的遗传性神经退行性疾病，由己糖胺酶A和B的β亚基缺乏引起，这两种溶酶体水解酶参与GM2神经节苷脂及相关代谢物的降解。目前，该疾病尚无有效的治疗方法。在此，我们表明腺病毒介导的β-己糖胺酶β亚基转移在感染桑德霍夫成纤维细胞后恢复了己糖胺酶A和己糖胺酶B的活性。在桑德霍夫病小鼠模型中进行脑内注射后，基因转移在测试的不同剂量下导致整个大脑的酶活性接近正常水平。向腺病毒载体中添加高渗浓度的甘露醇可增强载体在注射半球中的扩散。在注射高剂量载体的大脑中发现了腺病毒诱导的损伤，但在注射剂量低100倍的大脑中未检测到，即使存在甘露醇也是如此。我们的数据强调了将甘露醇添加到低剂量腺病毒载体中的优势，可实现高且弥散的转导效率而无病毒细胞毒性。
