TY - JOUR
T1 - Expression in blood cells may contribute to biochemical and pathological improvements after neonatal intravenous gene therapy for mucopolysaccharidosis VII in dogs
AU - Wang, Bin
AU - O'Malley, Thomas M.
AU - Xu, Lingfei
AU - Vite, Charles
AU - Wang, Ping
AU - O'Donnell, Patricia A.
AU - Ellinwood, N. Matthew
AU - Haskins, Mark E.
AU - Ponder, Katherine Parker
N1 - Funding Information:
This work was supported by DK54061 awarded to KPP, DK54481 and RR02512 awarded to MEH, the Washington University Digestive Diseases Research Core Center Grant (P30 52574), EY02687, DC04665, and Research to Prevent Blindness.
PY - 2006/1
Y1 - 2006/1
N2 - Mucopolysaccharidosis VII (MPS VII) is a lysosomal storage disease due to deficient activity of β-glucuronidase (GUSB) that results in accumulation of glycosaminoglycans in many organs. We have previously reported that neonatal intravenous injection of a gamma retroviral vector (RV) expressing canine GUSB resulted in transduction of hepatocytes, high levels of GUSB modified with mannose 6-phosphate in blood, and reduction in disease manifestations in the heart, bone, and eye. However, it was unclear if liver was the only site of expression, and the effect upon other organs was not assessed. We demonstrate here that blood cells from these RV-treated MPS VII dogs had substantial copies of RV DNA, and expressed the RNA at 2% of the level found in liver. Therefore, expression of GUSB in blood cells may synergize with uptake of GUSB from blood to reduce storage in organs. The RV-treated dogs had marked biochemical and pathological evidence of reduction in storage in liver, thymus, spleen, small intestines, and lung, and partial reduction of storage in kidney tubules. The brain had 6% of normal GUSB activity, and biochemical and pathological evidence of reduction in storage in neurons and other cell types. Thus, this neonatal gene therapy approach is effective and might be used in humans if it proves to be safe. Both secretion of enzyme into blood by hepatocytes, and expression in blood cells that migrate into organs, may contribute to correction of disease.
AB - Mucopolysaccharidosis VII (MPS VII) is a lysosomal storage disease due to deficient activity of β-glucuronidase (GUSB) that results in accumulation of glycosaminoglycans in many organs. We have previously reported that neonatal intravenous injection of a gamma retroviral vector (RV) expressing canine GUSB resulted in transduction of hepatocytes, high levels of GUSB modified with mannose 6-phosphate in blood, and reduction in disease manifestations in the heart, bone, and eye. However, it was unclear if liver was the only site of expression, and the effect upon other organs was not assessed. We demonstrate here that blood cells from these RV-treated MPS VII dogs had substantial copies of RV DNA, and expressed the RNA at 2% of the level found in liver. Therefore, expression of GUSB in blood cells may synergize with uptake of GUSB from blood to reduce storage in organs. The RV-treated dogs had marked biochemical and pathological evidence of reduction in storage in liver, thymus, spleen, small intestines, and lung, and partial reduction of storage in kidney tubules. The brain had 6% of normal GUSB activity, and biochemical and pathological evidence of reduction in storage in neurons and other cell types. Thus, this neonatal gene therapy approach is effective and might be used in humans if it proves to be safe. Both secretion of enzyme into blood by hepatocytes, and expression in blood cells that migrate into organs, may contribute to correction of disease.
KW - Gene therapy
KW - Glycosaminoglycan
KW - Lysosomal storage disease
KW - Mucopolysaccharidosis
KW - Retroviral vector
UR - http://www.scopus.com/inward/record.url?scp=29344470027&partnerID=8YFLogxK
U2 - 10.1016/j.ymgme.2005.08.014
DO - 10.1016/j.ymgme.2005.08.014
M3 - Article
C2 - 16275036
AN - SCOPUS:29344470027
SN - 1096-7192
VL - 87
SP - 8
EP - 21
JO - Molecular Genetics and Metabolism
JF - Molecular Genetics and Metabolism
IS - 1
ER -