TY - JOUR
T1 - Early versus late treatment of spinal cord compression with long-term intrathecal enzyme replacement therapy in canine mucopolysaccharidosis type I
AU - Dickson, Patricia I.
AU - Hanson, Stephen
AU - McEntee, Michael F.
AU - Vite, Charles H.
AU - Vogler, Carole A.
AU - Mlikotic, Anton
AU - Chen, Agnes H.
AU - Ponder, Katherine P.
AU - Haskins, Mark E.
AU - Tippin, Brigette L.
AU - Le, Steven Q.
AU - Passage, Merry B.
AU - Guerra, Catalina
AU - Dierenfeld, Ashley
AU - Jens, Jackie
AU - Snella, Elizabeth
AU - Kan, Shih hsin
AU - Ellinwood, N. Matthew
N1 - Funding Information:
We gratefully acknowledge the assistance of Sahil Shah, Dr. Larisa Troitskaya, and Jennifer Dancourt with experimental procedures at LA BioMed at Harbor-UCLA, and the many undergraduates who cared for and managed the ISU canine colony. Funding was provided by a grant from the National Institutes of Health ( NS054242 to PID), the Ryan Foundation (NME), the Center for Integrated Animal Genomics/ISU (NME), and the State of Iowa Board of Regents Battelle Platform and Infrastructure Grant Programs (NME). Additional affected and breeding animals were provided by Drs. Mark E. Haskins ( NIH RR002512 , University of Pennsylvania) and Katherine P. Ponder ( NIH DK066448 , Washington University St. Louis). Recombinant enzyme was donated by Biomarin Pharmaceutical Inc. (Novato, CA).
PY - 2010/10
Y1 - 2010/10
N2 - 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 12-15. 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 I 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.
AB - 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 12-15. 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 I 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.
KW - Enzyme replacement therapy
KW - Hurler
KW - Intrathecal
KW - Lysosomal storage disease
KW - Mucopolysaccharidosis
KW - Spinal cord compression
UR - http://www.scopus.com/inward/record.url?scp=77957237019&partnerID=8YFLogxK
U2 - 10.1016/j.ymgme.2010.06.020
DO - 10.1016/j.ymgme.2010.06.020
M3 - Article
C2 - 20655780
AN - SCOPUS:77957237019
VL - 101
SP - 115
EP - 122
JO - Molecular Genetics and Metabolism
JF - Molecular Genetics and Metabolism
SN - 1096-7192
IS - 2-3
ER -