TY - JOUR
T1 - Intrathecal enzyme replacement therapy
T2 - Successful treatment of brain disease via the cerebrospinal fluid
AU - Dickson, Patricia
AU - McEntee, Michael
AU - Vogler, Carole
AU - Le, Steven
AU - Levy, Beth
AU - Peinovich, Maryn
AU - Hanson, Stephen
AU - Passage, Merry
AU - Kakkis, Emil
N1 - Funding Information:
Funding provided by grants from the Ryan Foundation and BioMarin Pharmaceutical, Inc. We thank Rita Esquivel, Hayden Manuel, Catherine Jabagat, Catalina Guerra, Sarah Snider and Dan Garner for their technical assistance. We thank Karen Russell, DVM, at Texas A&M Department of Veterinary Pathobiology for assistance with canine laboratory specimens.
PY - 2007/5
Y1 - 2007/5
N2 - Treatment of brain disease with recombinant proteins is difficult due to the blood-brain barrier. As an alternative to direct injections into the brain, we studied whether application of high concentrations of therapeutic enzymes via intrathecal (IT) injections could successfully drive uptake across the ependyma to treat brain disease. We studied IT enzyme replacement therapy with recombinant human iduronidase (rhIDU) in canine mucopolysaccharidosis I (MPS I, Hurler syndrome), a lysosomal storage disorder with brain and meningeal involvement. Monthly or quarterly IT treatment regimens with rhIDU achieved supranormal iduronidase enzyme levels in the brain, spinal cord, and spinal meninges. All regimens normalized total brain glycosaminoglycan (GAG) storage and reduced spinal meningeal GAG storage by 58-70%. The improvement in GAG storage levels persisted three months after the final IT dose. The successful use of enzyme therapy via the CSF represents a potentially useful approach for lysosomal storage disorders.
AB - Treatment of brain disease with recombinant proteins is difficult due to the blood-brain barrier. As an alternative to direct injections into the brain, we studied whether application of high concentrations of therapeutic enzymes via intrathecal (IT) injections could successfully drive uptake across the ependyma to treat brain disease. We studied IT enzyme replacement therapy with recombinant human iduronidase (rhIDU) in canine mucopolysaccharidosis I (MPS I, Hurler syndrome), a lysosomal storage disorder with brain and meningeal involvement. Monthly or quarterly IT treatment regimens with rhIDU achieved supranormal iduronidase enzyme levels in the brain, spinal cord, and spinal meninges. All regimens normalized total brain glycosaminoglycan (GAG) storage and reduced spinal meningeal GAG storage by 58-70%. The improvement in GAG storage levels persisted three months after the final IT dose. The successful use of enzyme therapy via the CSF represents a potentially useful approach for lysosomal storage disorders.
KW - Central nervous system
KW - Cerebrospinal fluid
KW - Enzyme replacement therapy
KW - Hurler
KW - Hurler-Scheie
KW - Intrathecal
KW - Lysosomal storage disorder
KW - Mucopolysaccharidosis I
KW - Pachymeningitis
KW - Scheie
UR - http://www.scopus.com/inward/record.url?scp=34047267343&partnerID=8YFLogxK
U2 - 10.1016/j.ymgme.2006.12.012
DO - 10.1016/j.ymgme.2006.12.012
M3 - Article
C2 - 17321776
AN - SCOPUS:34047267343
SN - 1096-7192
VL - 91
SP - 61
EP - 68
JO - Molecular Genetics and Metabolism
JF - Molecular Genetics and Metabolism
IS - 1
ER -