Gene Therapy Ameliorates Cardiovascular Disease in Dogs With Mucopolysaccharidosis VII

Abstract

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...

Cardiac manifestations in the mouse model of mucopolysaccharidosis I

“…Liu et al [32] used a liver-targeted retroviral vector, and demonstrated complete normalization of heart biochemistry, structure and function at the higher dose of the vector. The same liver-targeted retroviral vector had shown excellent results in correcting the cardiovascular disease of the canine model of MPS VII (β-glucuronidase deficiency) [33]. Using a lentiviral vector, Domenico et al [34] restored only a low level of enzyme activity in heart or any tissue other than liver or spleen.…”

Carotid Intima-Media thickness is increased in patients with mucopolysaccharidoses

“…Prospective, longitudinal studies are also planned to determine if increased C-IMT in MPS patients correlates, via measurement of arterial elasticity and postischemic flow-mediated dilatation, with vascular endothelial dysfunction and subsequent development of cardiovascular events. Canine and murine MPS animal models, both of which manifest endothelial GAG storage [26][27][28], will also be studied for differences in patterns of arterial endothelial protein expression that may help predict C-IMT thickening and cardiovascular disease in human MPS patients. • Carotid IMT of mucopolysaccharidosis cohort was significantly greater than controls…”

Large animal models and gene therapy

“…Important clinical signs of disease, such as cardiac abnormalities, were absent or minimal. 32 There was marked improvement in the growth of treated dogs, and the skeletal disease was improved in the limbs. 30,31 The dogs have remained ambulatory to 5 years, versus untreated affected dogs, which are unable to stand or walk by the age of 6 months.…”