TY - JOUR
T1 - Impact of high-dose, chemically modified sulfamidase on pathology in a murine model of MPS IIIA
AU - Rozaklis, Tina
AU - Beard, Helen
AU - Hassiotis, Sofia
AU - Garcia, Antony R.
AU - Tonini, Matthew
AU - Luck, Amanda
AU - Pan, Jing
AU - Lamsa, Justin C.
AU - Hopwood, John J.
AU - Hemsley, Kim M.
N1 - Funding Information:
Role of funding sources: The study was primarily funded by the Sanfilippo Children's Research Foundation (SCRF; grant awarded to KHM and JJH). The SCRF did not have any role in study design, data collection, data analysis, interpretation of data, writing of the report or in the decision to submit the paper for publication. The every-other-day study was conducted and funded by Shire Human Genetic Therapies, who provided the mouse tissues to KMH and JJH for analysis. Shire HGT also provided rhSGSH for all experiments outlined in this manuscript.
PY - 2011/7
Y1 - 2011/7
N2 - Mucopolysaccharidosis type IIIA (MPS IIIA) is a neurodegenerative lysosomal storage disorder that results from a deficiency of sulfamidase (N-sulfoglucosamine sulfohydrolase), with consequential accumulation of its substrate, partially degraded heparan sulfate. Conventional doses (e.g. 1. mg/kg) of intravenously delivered recombinant human sulfamidase (rhSGSH) do not improve neuropathology in MPS IIIA mice due to an inability to traverse the blood-brain barrier; however high-dose treatment or administration of enzyme that has been chemically modified to remove mannose-6-phosphate glycans has been shown to reduce neuropathology in related animal models. We have combined these approaches to evaluate the ability of 1, 5, 10 or 20. mg/kg of similarly chemically modified or unmodified rhSGSH to reduce neuropathology following repeated intravenous delivery to adult MPS IIIA mice. rhSGSH was detected in brain homogenates from mice treated with all doses of modified rhSGSH and those receiving the two higher doses of unmodified rhSGSH, albeit at significantly lower levels. Immunohistochemically, rhSGSH visualized in the brain was localized to the endothelium, meninges and choroid plexus, with no convincing punctate intra-neuronal staining seen. This presumably underlies the failure of the treatment to reduce the relative level of a heparan sulfate-derived oligosaccharide (GlcNS-UA), or secondarily stored substrates that accumulate in MPS IIIA brain cells. However, modification of rhSGSH significantly increased its effectiveness in degrading GlcNS-UA in non-CNS tissues, potentially as a result of its reduced plasma clearance. If this observation is generally applicable, chemical modification may permit the use of significantly lower doses of lysosomal enzymes in patients currently receiving intravenous enzyme replacement therapy.
AB - Mucopolysaccharidosis type IIIA (MPS IIIA) is a neurodegenerative lysosomal storage disorder that results from a deficiency of sulfamidase (N-sulfoglucosamine sulfohydrolase), with consequential accumulation of its substrate, partially degraded heparan sulfate. Conventional doses (e.g. 1. mg/kg) of intravenously delivered recombinant human sulfamidase (rhSGSH) do not improve neuropathology in MPS IIIA mice due to an inability to traverse the blood-brain barrier; however high-dose treatment or administration of enzyme that has been chemically modified to remove mannose-6-phosphate glycans has been shown to reduce neuropathology in related animal models. We have combined these approaches to evaluate the ability of 1, 5, 10 or 20. mg/kg of similarly chemically modified or unmodified rhSGSH to reduce neuropathology following repeated intravenous delivery to adult MPS IIIA mice. rhSGSH was detected in brain homogenates from mice treated with all doses of modified rhSGSH and those receiving the two higher doses of unmodified rhSGSH, albeit at significantly lower levels. Immunohistochemically, rhSGSH visualized in the brain was localized to the endothelium, meninges and choroid plexus, with no convincing punctate intra-neuronal staining seen. This presumably underlies the failure of the treatment to reduce the relative level of a heparan sulfate-derived oligosaccharide (GlcNS-UA), or secondarily stored substrates that accumulate in MPS IIIA brain cells. However, modification of rhSGSH significantly increased its effectiveness in degrading GlcNS-UA in non-CNS tissues, potentially as a result of its reduced plasma clearance. If this observation is generally applicable, chemical modification may permit the use of significantly lower doses of lysosomal enzymes in patients currently receiving intravenous enzyme replacement therapy.
KW - Brain
KW - Enzyme replacement therapy
KW - Mouse
KW - Mucopolysaccharidosis
KW - Sanfilippo
UR - http://www.scopus.com/inward/record.url?scp=79958024590&partnerID=8YFLogxK
U2 - 10.1016/j.expneurol.2011.04.004
DO - 10.1016/j.expneurol.2011.04.004
M3 - Article
C2 - 21515264
AN - SCOPUS:79958024590
SN - 0014-4886
VL - 230
SP - 123
EP - 130
JO - Experimental Neurology
JF - Experimental Neurology
IS - 1
ER -