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(Circulation. 2004;110:815-820.)
© 2004 American Heart Association, Inc.

Original Articles

Gene Therapy Ameliorates Cardiovascular Disease in Dogs With Mucopolysaccharidosis VII

M.M. Sleeper, VMD; B. Fornasari, DVM; N.M. Ellinwood, DVM, PhD; M.A. Weil, AS; J. Melniczek, VMD; T.M. O’Malley, BS; C.D. Sammarco, BVSc, MRCVS; L. Xu, MD; K.P. Ponder, MD; M.E. Haskins, VMD, PhD

From the Departments of Clinical Studies (M.M.S.) and Pathobiology (B.F., N.M.E., M.A.W., J.M., T.M.O., M.E.H.), School of Veterinary Medicine, University of Pennsylvania, Philadelphia; Red Bank Veterinary Referral Center, Red Bank, NJ (C.D.S.); and the Departments of Internal Medicine and Biochemistry and Molecular Biophysics, Washington University School of Medicine, St Louis, Mo (L.X., K.P.P.).

Correspondence to Dr M. Sleeper, Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104. E-mail sleeper{at}vet.upenn.edu

Received August 29, 2003; de novo received December 23, 2003; revision received April 8, 2004; accepted April 27, 2004.

Background— Mucopolysaccharidosis VII (MPS VII) is a lysosomal storage disease caused by deficient ß-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 • gene therapy • lysosomes • mucopolysaccharidosis