Abstract 15413: Comparison of Vector Type and Timing of Gene Therapy to Correct Cardiovascular Manifestations of Mucopolysaccharidosis VII.
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 significant cause of morbidity and mortality with GAG accumulation in heart valves and arterial smooth muscle cells producing mitral and aortic valve thickening, and aortic root dilation. We previously reported (Circulation 110:815-820, 2004) IV injection of a retroviral (RV) vector expressing GUSB into neonatal MPS VII dogs resulted in stable GUSB activity. Here we compare the efficacy of gene transfer at 3 days and 7 weeks of age using a retroviral vector (RV3d [n=13] to RV7w [n=7]), and to an adeno-associated viral vector (AAV3d [n=7] and AAV7w [n=8]). Clinical findings, echocardiography, and enzyme activity were compared between 4 and 8 months of age to untreated, age matched [n=9] MPS VII dogs. Mitral regurgitation murmurs were less in all treated dogs except the AAV7w dogs (23% of RV3d, 29% of RV7w, 29% of AAV3d, 63% of AAV7w treated dogs and 44% of MPS VII untreated dogs). Mitral and aortic valve thickening (MVT, AoVT), regurgitation (MR, AR) and aortic root dilation (Aodil) were scored 0-4 (0 being none or normal; 4 representing severe thickening, leakage, or dilation. Echocardiography scores were most improved in the RV3d group compared to the untreated dogs with all variables reaching significance except MR (MVT, p=0.2, AOdil p=0.0008, AoVT p=0.041, AR p=0, MR p=0.99). Echocardiography scores of the RV7w dogs were not significantly different from the untreated group; the 2 AAV treated groups were only significantly improved in AR (p=0 and p=0). GUSB serum activity was improved in all treated groups measuring 1604, 74, 125, and 81 U/mL in the RV3d, AAV3d, RV7w, AAV7 groups, respectively (untreated dogs; 0.3 U/mL). We conclude that gene therapy with RV and AAV vectors at 3d and 7w of age improved cardiac manifestations in MPS VII dogs. However, neonatal RV gene therapy achieved the highest serum GUSB activity, and resulted in the most improved echocardiographic indices.
- © 2010 by American Heart Association, Inc.