TY - JOUR
T1 - Evaluation of pathological manifestations of disease in mucopolysaccharidosis VII mice after neonatal hepatic gene therapy
AU - Xu, Lingfei
AU - Mango, Robert L.
AU - Sands, Mark S.
AU - Ellinwood, N. Matthew
AU - Ponder, Katherine Parker
N1 - Funding Information:
We thank Marie Roberts for breeding of MPS VII mice and Carole Vogler (St. Louis University School of Medicine) for assistance with pathological analyses. This work was supported by the National Institutes of Health (R01 DK54061 and K02 DK02575 awarded to K.P.P., DK57586 and HD35671 awarded to M.S.S., DK54481 awarded to M.E.H.) and a Washington University Digestive Diseases Research Core Center grant (P30 DK 52574). Robert Mango was supported by an HHMI fellowship and N. Matthew Ellinwood by training grant RR T32-07063.
PY - 2002/12/1
Y1 - 2002/12/1
N2 - Mucopolysaccharidosis VII (MPS VII) is a lysosomal storage disease caused by β-glucuronidase (GUSB) deficiency. Intravenous injection of a retroviral vector expressing canine GUSB into neonatal MPS VII mice resulted in transduction of 6 to 35% of hepatocytes, which secreted GUSB into blood. Serum GUSB activity was stable for 6 months at 600 (low expression) to 10,000 (high expression) U/ml, and enzyme was modified appropriately with mannose 6-phosphate. The average serum GUSB activity (3531 U/ml) is the highest long-term expression reported for MPS VII mice after gene therapy. Secreted enzyme was taken up by other tissues, as the average enzyme activity was >13% of normal in somatic organs and 2% of normal in brain. Low expression markedly reduced histopathological evidence of lysosomal storage in liver, spleen, kidney, small intestine, neurons, and glial cells. High expression appeared to be more effective than low expression at reducing lysosomal storage in aorta, heart valves, thymus, bronchial epithelium, cornea, and retinal pigmented epithelium. Future experiments will determine if greater pathological improvements will consistently be observed in retrovirus-treated MPS VII mice with higher serum GUSB activity relative to animals with lower activity and if these result in clinical benefits.
AB - Mucopolysaccharidosis VII (MPS VII) is a lysosomal storage disease caused by β-glucuronidase (GUSB) deficiency. Intravenous injection of a retroviral vector expressing canine GUSB into neonatal MPS VII mice resulted in transduction of 6 to 35% of hepatocytes, which secreted GUSB into blood. Serum GUSB activity was stable for 6 months at 600 (low expression) to 10,000 (high expression) U/ml, and enzyme was modified appropriately with mannose 6-phosphate. The average serum GUSB activity (3531 U/ml) is the highest long-term expression reported for MPS VII mice after gene therapy. Secreted enzyme was taken up by other tissues, as the average enzyme activity was >13% of normal in somatic organs and 2% of normal in brain. Low expression markedly reduced histopathological evidence of lysosomal storage in liver, spleen, kidney, small intestine, neurons, and glial cells. High expression appeared to be more effective than low expression at reducing lysosomal storage in aorta, heart valves, thymus, bronchial epithelium, cornea, and retinal pigmented epithelium. Future experiments will determine if greater pathological improvements will consistently be observed in retrovirus-treated MPS VII mice with higher serum GUSB activity relative to animals with lower activity and if these result in clinical benefits.
KW - Gene therapy
KW - Glycosaminoglycans
KW - Liver
KW - Lysosomal storage disease
KW - Mucopolysaccharidosis
KW - Neonatal
KW - Retroviral vector
KW - β-glucuronidase
UR - http://www.scopus.com/inward/record.url?scp=0036932904&partnerID=8YFLogxK
U2 - 10.1006/mthe.2002.0809
DO - 10.1006/mthe.2002.0809
M3 - Review article
C2 - 12498771
AN - SCOPUS:0036932904
SN - 1525-0016
VL - 6
SP - 745
EP - 758
JO - Molecular Therapy
JF - Molecular Therapy
IS - 6
ER -