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Background-Mucopolysaccharidosis VII (MPS VII) is a lysosomal storage disease caused by deficient ␤-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. Methods and Results-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. Conclusions-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. Key Words: cardiovascular diseases Ⅲ gene therapy Ⅲ lysosomes Ⅲ mucopolysaccharidosis T he mucopolysaccharidoses (MPS) are a family of lysosomal storage diseases resulting from defective catabolism of glycosaminoglycans (GAGs) by 1 of 11 enzymes. 1,2 In humans, the most common cardiovascular lesion, regardless of MPS type, is thickening of the mitral valve with regurgitation or stenosis.3 Aortic valve thickening and hypertrophic cardiomyopathy are the next most common lesions, with endocardial thickening and dilated cardiomyopathy also recognized. 3 GAGs accumulate in the valve leaflets, with secondary fibrosis and nodular deformation. Primary myocardial involvement and infiltration of the coronary arteries with GAGs can also occur. 4 Cardiac involvement is present in most patients with MPS, and the lesions are progressive, with risk of death as a result of congestive heart failure. 3 A colony of MPS VII (␤-glucuronidase [GUSB]-deficient) dogs 5 have a mutation resulting in a single amino acid substitution, and cardiac abnormalities in affected dogs have been reported previously. 6,7 Enzyme replacement therapy, the intravenous injection of normal enzyme, 8 has been successful in MPS VI mice, MPS I dogs 9 and cats, 10 and human MPS I patients 11 ; however, cardiac function was not specifically evaluated. 12 Bone marrow transplantation (BMT) has been effective in MPS VII dogs 6 and also appeared to be beneficial in some MPS I, IV, and VI children. 13,14 Cardiac lysosomal storage was reduced in t...

Summary:The genetic mucopolysaccharidoses (MPS) are a family of lysosomal storage diseases resulting from defective catabolism of glycosaminoglycans (GAGs). Echocardiographic abnormalities in dogs with MPS type VII (Sly syndrome, ␤-glucuronidase deficiency) included mitral valve thickening and insufficiency, large aortic dimensions in both the long and short axes, and thickened aortic valves. Grossly, at post mortem examination, there was nodular thickening of the mitral valve, a prominent ductus diverticulum, and a dilated aorta with thickened walls. Histologically, cytoplasmic vacuolation was seen in cells of the mitral valves, coronary arteries, and aorta. By electron microscopy, the cells of the mitral valve were packed with electron-lucent cytoplasmic vacuoles. The mean residual activity of ␤-glucuronidase in the aorta and myocardium was Ͻ1% of normal, the mean hexosaminidase A activity Ͼ2.5 times normal, and the mean GAG concentrations more than twice normal. In three MPS VII dogs that received heterologous BMT at 6 weeks of age, the echocardiographic abnormalities were improved, and the histopathologic and ultrastructural pathology was reduced. In the aorta and myocardium, the mean ␤-glucuronidase activity of the BMT group was 4.5% and 11% of normal, respectively, and the hexosaminidase A activity and GAG concentrations were normalized. Bone Marrow Transplantation (2000) 25, 1289-1297.

The objective of this prospective study was to determine the prevalence of echocardiographic evidence of heart disease in apparently healthy cats with heart murmurs. Thirty-two privately owned domestic cats were examined. All cats were considered healthy on the basis of history and physical examination, except for the finding of a heart murmur on auscultation. Cats on any medications (besides regular flea, tick and heartworm preventative) or that were pregnant or lactating were excluded from this study. The prevalence of echocardiographic evidence of heart disease in this population of cats was 53%. Therefore, identification of a heart murmur on routine physical examination in apparently healthy cats warrants further investigation.

Sixty-four dogs were treated with single-agent doxorubicin (DOX) for presumptive cardiac hemangiosarcoma (cHSA). The objective response rate (CR + PR) was 41%, and the biologic response rate (CR + PR + SD), or clinical benefit, was 68%. The median progression-free survival (PFS) for treated dogs was 66 days. The median survival time (MST) for this group was 116 days and was significantly improved compared to a MST of 12 days for untreated control dogs (P = 0.0001). Biologic response was significantly associated with improved PFS (P < 0.0001) and OS (P < 0.0001). Univariate analysis identified larger tumour size as a variable negatively associated with PFS. The high rate of clinical benefit and improved MST suggest that DOX has activity in canine cHSA.