TY - JOUR
T1 - Neonatal gene therapy with a gamma retroviral vector in mucopolysaccharidosis VI cats
AU - Ponder, Katherine P.
AU - O'Malley, Thomas M.
AU - Wang, Ping
AU - O'Donnell, Patricia A.
AU - Traas, Anne M.
AU - Knox, Van W.
AU - Aguirre, Gustavo A.
AU - Ellinwood, N. Matthew
AU - Metcalf, Jason A.
AU - Wang, Bin
AU - Parkinson-Lawrence, Emma J.
AU - Sleeper, Meg M.
AU - Brooks, Doug A.
AU - Hopwood, John J.
AU - Haskins, Mark E.
N1 - Funding Information:
From the University of Pennsylvania, we thank James Hayden for facial illustrations, Meg Weil and Tracey Sikora for the videos, the memory of Karyn Cullen for assistance with animal care, and veterinary students and the University Laboratory Animal Resources staff for assistance with animal care. This work was supported by grants from the National MPS Society awarded to M.E.H. and K.P.P., grants from the National Institutes of Health (HD061879 awarded to K.P.P., DK25759 and RR02512 awarded to M.E.H., RR07063 awarded to N.M.E.), and grants from the National Health and Medical Research Council of Australia awarded to J.J.H.
PY - 2012/5
Y1 - 2012/5
N2 - Mucopolysaccharidosis (MPS) VI is due to a deficiency in the activity of N-acetylgalactosamine 4-sulfatase (4S), also known as arylsulfatase B. Previously, retroviral vector (RV)-mediated neonatal gene therapy reduced the clinical manifestations of MPS I and MPS VII in mice and dogs. However, sulfatases require post-translational modification by sulfatase-modifying factors. MPS VI cats were injected intravenously (i.v.) with a gamma RV-expressing feline 4S, resulting in 5 ± 3 copies of RV per 100 cells in liver. Liver and serum 4S activity were 1,450 ± 1,720 U/mg (26-fold normal) and 107 ± 60 U/ml (13-fold normal), respectively, and were directly proportional to the liver 4S protein levels for individual cats. This study suggests that sulfatase-modifying factor (SUMF) activity in liver was sufficient to result in active enzyme despite overexpression of 4S. RV-treated MPS VI cats achieved higher body weights and longer appendicular skeleton lengths, had reduced articular cartilage erosion, and reduced aortic valve thickening and aortic dilatation compared with untreated MPS VI cats, although cervical vertebral bone lengths were not improved. This demonstrates that therapeutic expression of a functional sulfatase protein can be achieved with neonatal gene therapy using a gamma RV, but some aspects of bone disease remain difficult to treat.
AB - Mucopolysaccharidosis (MPS) VI is due to a deficiency in the activity of N-acetylgalactosamine 4-sulfatase (4S), also known as arylsulfatase B. Previously, retroviral vector (RV)-mediated neonatal gene therapy reduced the clinical manifestations of MPS I and MPS VII in mice and dogs. However, sulfatases require post-translational modification by sulfatase-modifying factors. MPS VI cats were injected intravenously (i.v.) with a gamma RV-expressing feline 4S, resulting in 5 ± 3 copies of RV per 100 cells in liver. Liver and serum 4S activity were 1,450 ± 1,720 U/mg (26-fold normal) and 107 ± 60 U/ml (13-fold normal), respectively, and were directly proportional to the liver 4S protein levels for individual cats. This study suggests that sulfatase-modifying factor (SUMF) activity in liver was sufficient to result in active enzyme despite overexpression of 4S. RV-treated MPS VI cats achieved higher body weights and longer appendicular skeleton lengths, had reduced articular cartilage erosion, and reduced aortic valve thickening and aortic dilatation compared with untreated MPS VI cats, although cervical vertebral bone lengths were not improved. This demonstrates that therapeutic expression of a functional sulfatase protein can be achieved with neonatal gene therapy using a gamma RV, but some aspects of bone disease remain difficult to treat.
UR - http://www.scopus.com/inward/record.url?scp=84862804825&partnerID=8YFLogxK
U2 - 10.1038/mt.2012.9
DO - 10.1038/mt.2012.9
M3 - Article
C2 - 22395531
AN - SCOPUS:84862804825
SN - 1525-0016
VL - 20
SP - 898
EP - 907
JO - Molecular Therapy
JF - Molecular Therapy
IS - 5
ER -