Effects of bone marrow transplantation on the cardiovascular abnormalities in canine mucopolysaccharidosis VII

Abstract

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.

Electrocardiographic and other cardiac anomalies in β-glucuronidase-null mice corrected by nonablative neonatal marrow transplantation

“…Valve improvements and disappearance of storage in both the aorta and heart valves are noted after retroviral gene transfer therapy in the murine MPSVII neonate (30). These changes are consistent with gene therapy results in MPSVII newborn dogs where mitral valve regurgitation assessed by echocardiography was minimal or absent by 8-9 months posttreatment (49). Here, the distension of the dorsal aortic root and storage in the intimal and medial layers of the aorta and in the conduction system myocytes are detected in both treated and untreated mice and likely have little effect on the ECG pattern.…”

Gene Therapy Ameliorates Cardiovascular Disease in Dogs With Mucopolysaccharidosis VII

“…Enzyme replacement therapy and BMT have both been successful in reducing the cardiac manifestations of MPS in animals and humans. 6,[22][23][24][25] However, enzyme replacement therapy is expensive and requires frequent, lifelong administration, and BMT has traditionally resulted in substantial risks for patients, 26,27 although recent development of nonablative marrow transplant with high cell dosage has proved to be effective and safer. 16 One child with MPS VII has been studied after BMT therapy at 12 years of age.…”

“…6,18,19 Activity was expressed as nanomoles of 4-methylumbelliferone released per hour per milligram protein.…”

“…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.…”

“…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 the MPS VII mouse after BMT, and GUSB activity was 53% of normal.…”