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.