Gene therapy ameliorates cardiovascular disease in dogs with mucopolysaccharidosis VII

• Published in: Circulation (New York, N.Y.) Vol. 110; no. 7; pp. 815 - 820
• Main Authors: Sleeper, M M, Fornasari, B, Ellinwood, N M, Weil, M A, Melniczek, J, O'Malley, T M, Sammarco, C D, Xu, L, Ponder, K P, Haskins, M E
• Format: Journal Article
• Language: English
• Published: United States 17.08.2004
• Subjects: Animals; Animals, Newborn; Aorta - enzymology; Aortic Valve - pathology; beta-N-Acetylhexosaminidases - analysis; Cardiovascular Diseases - diagnostic imaging; Cardiovascular Diseases - etiology; Cardiovascular Diseases - prevention & control; Cardiovascular Diseases - veterinary; Disease Models, Animal; Dog Diseases - genetics; Dog Diseases - therapy; Dogs; Genetic Therapy - veterinary; Genetic Vectors - administration & dosage; Genetic Vectors - therapeutic use; Glucuronidase - analysis; Glucuronidase - genetics; Glucuronidase - physiology; Glycosaminoglycans - metabolism; Heart Valve Diseases - diagnostic imaging; Heart Valve Diseases - etiology; Heart Valve Diseases - pathology; Heart Valve Diseases - prevention & control; Heart Valve Diseases - veterinary; Hepatocytes - secretion; Injections, Intravenous; Lysosomes - enzymology; Mitral Valve - pathology; Mucopolysaccharidosis VII - complications; Mucopolysaccharidosis VII - enzymology; Mucopolysaccharidosis VII - therapy; Mucopolysaccharidosis VII - veterinary; Myocardium - enzymology; Myocytes, Cardiac - metabolism; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - physiology; Recombinant Fusion Proteins - secretion; Retroviridae - genetics; Ultrasonography
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/01.CIR.0000138747.82487.4B

Mucopolysaccharidosis VII (MPS VII) is a lysosomal storage disease caused by deficient beta-glucuronidase (GUSB) activity resulting in defective catabolism of glycosaminoglycans (GAGs). Cardiac disease is a major cause of death in MPS VII because of accumulation of GAGs in cardiovascular cells. Manifestations include cardiomyopathy, mitral and aortic valve thickening, and aortic root dilation and may cause death in the early months of life or may be compatible with a fairly normal lifespan. We previously reported that neonatal administration of a retroviral vector (RV) resulted in transduction of hepatocytes, which secreted GUSB into the blood and could be taken up by cells throughout the body. The goal of this study was to evaluate the effect on cardiac disease. Six MPS VII dogs were treated intravenously with an RV-expressing canine GUSB. Echocardiographic parameters, cardiovascular lesions, and biochemical parameters of these dogs were compared with those of normal and untreated MPS VII dogs. RV-treated dogs were markedly improved compared with untreated MPS VII dogs. Most RV-treated MPS VII dogs had mild or moderate mitral regurgitation at 4 to 5 months after birth, which improved or disappeared when evaluated at 9 to 11 and at 24 months. Similarly, mitral valve thickening present early in some animals disappeared over time, whereas aortic dilation and aortic valve thickening were absent at all times. Both myocardium and aorta had significant levels of GUSB and reduction in GAGs.