TY - JOUR
T1 - The effect of neonatal gene therapy with a gamma retroviral vector on cardiac valve disease in mucopolysaccharidosis VII dogs after a decade
AU - Bigg, Paul W.
AU - Sleeper, Meg M.
AU - O'Donnell, Patricia A.
AU - Liu, Yuli
AU - Wu, Susan
AU - Casal, Margret L.
AU - Haskins, Mark E.
AU - Ponder, Katherine P.
N1 - Funding Information:
Funding was provided by the National Institutes of Health ( DK054481 and P40 OD010939 awarded to MEH and HD061879 awarded to KPP), and the National MPS Society . Histology was supported by P30 DK52574.
PY - 2013/11
Y1 - 2013/11
N2 - Mucopolysaccharidosis VII (MPS VII) is due to deficient activity of the lysosomal enzyme β-glucuronidase (GUSB) and results in the accumulation of glycosaminoglycans (GAGs). This study determined the long-term effect of neonatal intravenous injection of a gamma retroviral vector (RV) on cardiac valve disease in MPS VII dogs. Transduced hepatocytes secreted GUSB into the blood for up to 11. years at levels similar to or greater than those achieved with enzyme replacement therapy (ERT). Valve regurgitation and thickening were scored from 0 (normal) to +. 4 (severely abnormal). At 1. year, untreated MPS VII dogs had mitral regurgitation, mitral valve thickening, aortic regurgitation, and aortic valve thickening scores of 2.3 ± 0.7, 2.3. ± 0.6, 1.8 ± 0.5, and 1.6 ± 0.7, respectively, which were higher than the values of 0.6 ± 0.1, 0.1 ± 0.4, 0.3 ± 0.8, and 0.1 ± 0.4, respectively, in treated MPS VII dogs. Treated MPS VII dogs maintained low aortic regurgitation and aortic valve thickening scores in their lifetime. Although mitral regurgitation and mitral valve thickening scores increased to 2.0 at ≥ 8. years of age in the treated MPS VII dogs, older normal dogs from the colony had similar scores, making it difficult to assess mitral valve disease. Older treated dogs had calcification within the mitral and the aortic valve annulus, while GUSB staining demonstrated enzyme activity within the mitral valve. We conclude that neonatal RV-mediated gene therapy reduced cardiac valve disease in MPS VII dogs for up to 11. years, and propose that neonatal initiation of ERT should have a similar effect.
AB - Mucopolysaccharidosis VII (MPS VII) is due to deficient activity of the lysosomal enzyme β-glucuronidase (GUSB) and results in the accumulation of glycosaminoglycans (GAGs). This study determined the long-term effect of neonatal intravenous injection of a gamma retroviral vector (RV) on cardiac valve disease in MPS VII dogs. Transduced hepatocytes secreted GUSB into the blood for up to 11. years at levels similar to or greater than those achieved with enzyme replacement therapy (ERT). Valve regurgitation and thickening were scored from 0 (normal) to +. 4 (severely abnormal). At 1. year, untreated MPS VII dogs had mitral regurgitation, mitral valve thickening, aortic regurgitation, and aortic valve thickening scores of 2.3 ± 0.7, 2.3. ± 0.6, 1.8 ± 0.5, and 1.6 ± 0.7, respectively, which were higher than the values of 0.6 ± 0.1, 0.1 ± 0.4, 0.3 ± 0.8, and 0.1 ± 0.4, respectively, in treated MPS VII dogs. Treated MPS VII dogs maintained low aortic regurgitation and aortic valve thickening scores in their lifetime. Although mitral regurgitation and mitral valve thickening scores increased to 2.0 at ≥ 8. years of age in the treated MPS VII dogs, older normal dogs from the colony had similar scores, making it difficult to assess mitral valve disease. Older treated dogs had calcification within the mitral and the aortic valve annulus, while GUSB staining demonstrated enzyme activity within the mitral valve. We conclude that neonatal RV-mediated gene therapy reduced cardiac valve disease in MPS VII dogs for up to 11. years, and propose that neonatal initiation of ERT should have a similar effect.
KW - Cardiac disease
KW - Gene therapy
KW - Lysosomal storage disease
KW - Mucopolysaccharidosis
KW - Retroviral vector
UR - http://www.scopus.com/inward/record.url?scp=84885434041&partnerID=8YFLogxK
U2 - 10.1016/j.ymgme.2013.06.015
DO - 10.1016/j.ymgme.2013.06.015
M3 - Article
C2 - 23860311
AN - SCOPUS:84885434041
SN - 1096-7192
VL - 110
SP - 311
EP - 318
JO - Molecular Genetics and Metabolism
JF - Molecular Genetics and Metabolism
IS - 3
ER -