Kakkis E, McEntee M, Vogler C, Le S, Levy B, Belichenko P, Mobley W, Dickson P, Hanson S, Passage M
Division of Medical Genetics, Department of Pediatrics, Harbor-UCLA Research and Education Institute, Torrance CA, USA.
Mol Genet Metab. 2004 Sep-Oct;83(1-2):163-74. doi: 10.1016/j.ymgme.2004.07.003.
Enzyme replacement therapy (ERT) has been developed for several lysosomal storage disorders, including mucopolysaccharidosis I (MPS I), and is effective at reducing lysosomal storage in many tissues and in ameliorating clinical disease. However, intravenous ERT does not adequately treat storage disease in the central nervous system (CNS), presumably due to effects of the blood-brain barrier on enzyme distribution. To circumvent this barrier, we studied whether intrathecal (IT) recombinant human alpha-L-iduronidase (rhIDU) could penetrate and treat the brain and meninges. An initial dose-response study showed that doses of 0.46-4.14 mg of IT rhIDU successfully penetrated the brain of normal dogs and reached tissue levels 5.6 to 18.9-fold normal overall and 2.7 to 5.9-fold normal in deep brain sections lacking CSF contact. To assess the efficacy and safety in treating lysosomal storage disease, four weekly doses of approximately 1 mg of IT rhIDU were administered to MPS I-affected dogs resulting in a mean 23- and 300-fold normal levels of iduronidase in total brain and meninges, respectively. Quantitative glycosaminoglycan (GAG) analysis showed that the IT treatment reduced mean total brain GAG to normal levels and achieved a 57% reduction in meningeal GAG levels accompanied by histologic improvement in lysosomal storage in all cell types. The dogs did develop a dose-dependent immune response against the recombinant human protein and a meningeal lymphocytic/plasmacytic infiltrate. The IT route of ERT administration may be an effective way to treat the CNS disease in MPS I and could be applicable to other lysosomal storage disorders.
酶替代疗法（ERT）已被开发用于多种溶酶体贮积症，包括黏多糖贮积症I型（MPS I），并且在减少许多组织中的溶酶体贮积以及改善临床疾病方面是有效的。然而，静脉内ERT并不能充分治疗中枢神经系统（CNS）中的贮积病，这可能是由于血脑屏障对酶分布的影响。为了绕过这一屏障，我们研究了鞘内注射（IT）重组人α-L-艾杜糖醛酸酶（rhIDU）是否能够穿透并治疗脑和脑膜。一项初始剂量反应研究表明，0.46 - 4.14 mg的IT rhIDU剂量成功穿透了正常犬的脑，并在总体上达到了正常组织水平的5.6至18.9倍，在缺乏脑脊液接触的深部脑切片中达到了正常水平的2.7至5.9倍。为了评估治疗溶酶体贮积病的疗效和安全性，对受MPS I影响的犬每周给予四次约1 mg的IT rhIDU，结果在全脑和脑膜中艾杜糖醛酸酶的平均水平分别达到了正常水平的23倍和300倍。定量糖胺聚糖（GAG）分析表明，IT治疗将全脑平均总GAG降低至正常水平，并使脑膜GAG水平降低了57%，同时所有细胞类型的溶酶体贮积在组织学上得到改善。这些犬确实产生了针对重组人蛋白的剂量依赖性免疫反应以及脑膜淋巴细胞/浆细胞浸润。ERT的IT给药途径可能是治疗MPS I中枢神经系统疾病的有效方法，并且可能适用于其他溶酶体贮积症。
