Early versus late treatment of spinal cord compression with long-term intrathecal enzyme replacement therapy in canine mucopolysaccharidosis type I

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 1215 months (Adult) and MPS I pups age 2-23 days (Early) to determine whether spinal cord compression could be reversed, stabilized, or prevented. Five treatment groups of MPS 1 dogs were evaluated (n=4 per group): IT + IV Adult. IV Adult, IT + IV Early, 0.58 mg/kg IV Early and 1.57 mg/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), 0.58 mg/kg IV Early (p=.002) and 1.57 mg/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 1.57 mg/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 12-15 months 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 0.58 mg/kg IV Early group; 2 of 3 dogs in the IT + IV Early group; and 0 of 4 dogs in the 1.57 mg/kg IV Early group by 12-18 months 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 (1.57 mg/kg weekly) appeared to prevent cord compression due to protrusion of spinal disks. (C) 2010 Elsevier Inc. All rights reserved.