TY - JOUR
T1 - Radiographic evaluation of bones and joints in mucopolysaccharidosis I and VII dogs after neonatal gene therapy
AU - Herati, Ramin Sedaghat
AU - Knox, Van W.
AU - O'Donnell, Patricia
AU - D'Angelo, Marina
AU - Haskins, Mark E.
AU - Ponder, Katherine P.
N1 - Funding Information:
This work was supported by the Ryan Foundation, the National MPS Society, and the National Institutes of Health ( DK66448 awarded to KPP, DK54481 awarded to MEH, and RR02512 awarded to MEH).
PY - 2008/11
Y1 - 2008/11
N2 - Mucopolysaccharidosis I (MPS I) and MPS VII are due to deficient activity of the glycosaminoglycan-degrading lysosomal enzymes α-l-iduronidase and β-glucuronidase, respectively, and result in abnormal bones and joints. Here, the severity of skeletal disease in MPS I and MPS VII dogs and the effects of neonatal gene therapy were evaluated. For untreated MPS VII dogs, the lengths of the second cervical vertebrae (C2) and the femur were only 56% and 84% of normal, respectively, and bone dysplasia and articular erosions, and joint subluxation were severe. Previously, we reported that neonatal intravenous injection of a retroviral vector (RV) with the appropriate gene resulted in expression in liver and blood cells, and high serum enzyme activity. In this study, we demonstrate that C2 and femurs of RV-treated MPS VII dogs were longer at 82% and 101% of normal, respectively, and there were partial improvements of qualitative abnormalities. For untreated MPS I dogs, the lengths of C2 and femurs (91% and 96% of normal, respectively) were not significantly different from normal dogs. Qualitative changes in MPS I bones and joints were generally modest and were partially improved with RV treatment, although cervical spine disease was severe and was difficult to correct with gene therapy in both models. The greater severity of skeletal disease in MPS VII than in MPS I dogs may reflect accumulation of chondroitin sulfate in cartilage in MPS VII, or could relate to the specific mutations. Neonatal RV-mediated gene therapy ameliorates, but does not prevent, skeletal disease in MPS I and MPS VII dogs.
AB - Mucopolysaccharidosis I (MPS I) and MPS VII are due to deficient activity of the glycosaminoglycan-degrading lysosomal enzymes α-l-iduronidase and β-glucuronidase, respectively, and result in abnormal bones and joints. Here, the severity of skeletal disease in MPS I and MPS VII dogs and the effects of neonatal gene therapy were evaluated. For untreated MPS VII dogs, the lengths of the second cervical vertebrae (C2) and the femur were only 56% and 84% of normal, respectively, and bone dysplasia and articular erosions, and joint subluxation were severe. Previously, we reported that neonatal intravenous injection of a retroviral vector (RV) with the appropriate gene resulted in expression in liver and blood cells, and high serum enzyme activity. In this study, we demonstrate that C2 and femurs of RV-treated MPS VII dogs were longer at 82% and 101% of normal, respectively, and there were partial improvements of qualitative abnormalities. For untreated MPS I dogs, the lengths of C2 and femurs (91% and 96% of normal, respectively) were not significantly different from normal dogs. Qualitative changes in MPS I bones and joints were generally modest and were partially improved with RV treatment, although cervical spine disease was severe and was difficult to correct with gene therapy in both models. The greater severity of skeletal disease in MPS VII than in MPS I dogs may reflect accumulation of chondroitin sulfate in cartilage in MPS VII, or could relate to the specific mutations. Neonatal RV-mediated gene therapy ameliorates, but does not prevent, skeletal disease in MPS I and MPS VII dogs.
KW - Dysostosis multiplex
KW - Gene therapy
KW - Glycosaminoglycan
KW - Lysosomal storage disease
KW - Mucopolysaccharidosis
KW - α-l-Iduronidase
KW - β-glucuronidase
UR - http://www.scopus.com/inward/record.url?scp=53749102830&partnerID=8YFLogxK
U2 - 10.1016/j.ymgme.2008.07.003
DO - 10.1016/j.ymgme.2008.07.003
M3 - Article
C2 - 18707908
AN - SCOPUS:53749102830
SN - 1096-7192
VL - 95
SP - 142
EP - 151
JO - Molecular genetics and metabolism
JF - Molecular genetics and metabolism
IS - 3
ER -