Evaluation of AAV vectors with tissue-specific or ubiquitous promoters in a mouse model of mucopolysaccharidosis type IVA

Mucopolysaccharidosis type IVA (MPS IVA) is caused by a deficiency of <i>N</i>-acetyl-galactosamine-6-sulfate sulfatase (GALNS), leading to the accumulation of keratan sulfate and chondroitin-6-sulfate and development of severe skeletal dysplasia. Enzyme replacement therapy and hematopoietic stem cell transplantation are current treatment options but have limited impact on bone lesions. In this study, we investigated adeno-associated virus (AAV)8 or AAV9 vectors with liver-specific thyroxine-binding globulin or liver-specific promoter-a modification of hAAT (LSPX), liver-muscle tandem (LMTP), liver-bone tandem (LBTP), and ubiquitous cytomegalovirus early enhancer/chicken β-actin (CAG) promoters in MPS IVA mice to compare therapeutic efficacy on biochemical markers and bone pathology. All vectors provided near- or supraphysiological levels of GALNS enzyme activity in plasma. Enzyme activities were also detected in various tissues, including bone. AAV9co-CAG, AAV9co-LMTP, and AAV9co-LBTP showed higher enzyme activities in the liver; however, AAV8co-CAG and AAV9co-LMTP have higher activities in most other tissues. All vectors normalized keratan sulfate levels in plasma, liver, and bone. Pathological analyses showed the reduction or complete absence of vacuolated cells in heart muscle and valves in all treated mice, while the AAV9co-LMTP vector most improved bone pathology. Overall, all studied vectors indicated a substantial improvement in biochemical parameters and pathology, and the AAV9co-LMTP vector demonstrated the best combined therapeutic efficacy.