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 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.
Dickson
Patricia I
PI
Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, 1124 W. Carson Street, Torrance, CA 90502, USA. pdickson@ucla.edu
Hanson
Stephen
S
McEntee
Michael F
MF
Vite
Charles H
CH
Vogler
Carole A
CA
Mlikotic
Anton
A
Chen
Agnes H
AH
Ponder
Katherine P
KP
Haskins
Mark E
ME
Tippin
Brigette L
BL
Le
Steven Q
SQ
Passage
Merry B
MB
Guerra
Catalina
C
Dierenfeld
Ashley
A
Jens
Jackie
J
Snella
Elizabeth
E
Kan
Shih-Hsin
SH
Ellinwood
N Matthew
NM
D000818:Animals; D004285:Dogs; D056947:Enzyme Replacement Therapy / Q000662:veterinary*; D006801:Humans; D007068:Iduronidase / Q000627:therapeutic use*; D007278:Injections, Spinal; D008279:Magnetic Resonance Imaging / Q000662:veterinary; D008059:Mucopolysaccharidosis I / Q000188:drug therapy* / Q000662:veterinary*; D013116:Spinal Cord / Q000473:pathology; D013117:Spinal Cord Compression / Q000188:drug therapy* / Q000473:pathology / Q000662:veterinary*
D007068:Iduronidase