Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, 1124 W. Carson Street, Torrance, CA 90502, USA.
Mol Genet Metab. 2010 Oct-Nov;101(2-3):115-22. doi: 10.1016/j.ymgme.2010.06.020. Epub 2010 Jul 23.
Enzyme replacement therapy (ERT) with intravenous recombinant human alpha-l-iduronidase (IV rhIDU) is a treatment for patients with mucopolysaccharidosis I (MPS I). Spinal cord compression develops in MPS I patients due in part to dural and leptomeningeal thickening from accumulated glycosaminoglycans (GAG). We tested long-term and every 3-month intrathecal (IT) and weekly IV rhIDU in MPS I dogs age 12-15months (Adult) and MPS I pups age 2-23days (Early) to determine whether spinal cord compression could be reversed, stabilized, or prevented. Five treatment groups of MPS I dogs were evaluated (n=4 per group): IT+IV Adult, IV Adult, IT + IV Early, 0.58mg/kg IV Early and 1.57mg/kg IV Early. IT + IV rhIDU (Adult and Early) led to very high iduronidase levels in cervical, thoracic, and lumber spinal meninges (3600-29,000% of normal), while IV rhIDU alone (Adult and Early) led to levels that were 8.2-176% of normal. GAG storage was significantly reduced from untreated levels in spinal meninges of IT + IV Early (p<.001), IT+IV Adult (p=.001), 0.58mg/kg IV Early (p=.002) and 1.57mg/kg IV Early (p<.001) treatment groups. Treatment of dogs shortly after birth with IT+IV rhIDU (IT + IV Early) led to normal to near-normal GAG levels in the meninges and histologic absence of storage vacuoles. Lysosomal storage was reduced in spinal anterior horn cells in 1.57mg/kg IV Early and IT + IV Early animals. All dogs in IT + IV Adult and IV Adult groups had compression of their spinal cord at 12-15months of age determined by magnetic resonance imaging and was due to protrusion of spinal disks into the canal. Cord compression developed in 3 of 4 dogs in the 0.58mg/kg IV Early group; 2 of 3 dogs in the IT + IV Early group; and 0 of 4 dogs in the 1.57mg/kg IV Early group by 12-18months of age. IT + IV rhIDU was more effective than IV rhIDU alone for treatment of meningeal storage, and it prevented meningeal GAG accumulation when begun early. High-dose IV rhIDU from birth (1.57mg/kg weekly) appeared to prevent cord compression due to protrusion of spinal disks.
酶替代疗法（ERT）用静脉重组人α-L-艾杜糖苷酸酶（IV rhIDU）是治疗黏多糖贮积症 I 型（MPS I）患者的方法。MPS I 患者的脊髓压迫部分是由于鞘内和软脑膜增厚导致积累的糖胺聚糖（GAG）所致。我们测试了长期和每 3 个月鞘内（IT）和每周 IV rhIDU 在 12-15 月龄（成人）和 2-23 天（早期）MPS I 犬中的作用，以确定是否可以逆转、稳定或预防脊髓压迫。评估了 5 个 MPS I 犬治疗组（每组 4 只）：IT+IV 成人、IV 成人、IT+IV 早期、0.58mg/kg IV 早期和 1.57mg/kg IV 早期。IT+IV rhIDU（成人和早期）导致颈、胸和腰椎脑膜中的艾杜糖苷酸酶水平非常高（正常的 3600-29000%），而单独使用 IV rhIDU（成人和早期）则导致正常水平的 8.2-176%。鞘内 IT+IV 早期（p<.001）、IT+IV 成人（p=.001）、0.58mg/kg IV 早期（p=.002）和 1.57mg/kg IV 早期（p<.001）治疗组的 GAG 储存量与未经治疗的水平相比显著降低。出生后不久用 IT+IV rhIDU（IT+IV 早期）治疗的犬在脑膜中的 GAG 水平正常或接近正常，并且组织学上不存在储存空泡。1.57mg/kg IV 早期和 IT+IV 早期动物的脊髓前角细胞中的溶酶体储存减少。在 12-15 月龄时，通过磁共振成像确定 IT+IV 成人和 IV 成人组的所有犬均存在脊髓压迫，这是由于椎间盘向椎管突出所致。0.58mg/kg IV 早期组中有 3 只犬中的 3 只犬、IT+IV 早期组中有 2 只犬中的 2 只犬和 1.57mg/kg IV 早期组中有 4 只犬中的 0 只犬在 12-18 月龄时发生脊髓压迫。IT+IV rhIDU 比单独使用 IV rhIDU 更有效治疗脑膜储存，并且当早期开始时可防止脑膜 GAG 积累。从出生开始每周 1.57mg/kg 的高剂量 IV rhIDU 似乎可预防由于椎间盘突出引起的脊髓压迫。
