205. AAV-Mediated Gene Transfer to Muscle and Liver of MPS VI Animal Models

Abstract

Mucopolysaccharidosis VI (MPS VI) or Maroteaux-Lamy syndrome is a lysosomal storage disease caused by deficient N-acetylgalactosamine-4-sulfatase (arylsulfatase B, ARSB) activity and characterized by skeletal dysplasia, corneal clouding, hepatosplenomegaly and heart valve lesions. No central nervous system involvement is associated with MPS VI. ARSB is secreted from normal cells and up taken by adjacent cells, which is the basis for various experimental therapies, such as bone marrow transplantation (BMT), enzyme replacement therapy (ERT), and more recently gene therapy. Vectors derived from the small non-pathogenic adeno-associated virus (AAV) hold great promise for in vivo gene transfer to several organs including muscle or liver, which can be converted to enzyme |[ldquo]|factories|[rdquo]| for systemic production of ARSB. We are currently testing the ability of AAV vectors to prevent or rescue the MPS VI phenotype in two spontaneous animal models: a rat with a frameshift and a cat with a missense mutation in the Arsb gene, mimicking mutations found in the majority of MPS VI patients. Newborn MPS VI cats and rats have been injected into muscle or intravenously with AAV2/1-CMV-fArsb or AAV2/8-TBG-fArsb, respectively. Similar levels of circulating ARSB were obtained following liver or muscle gene transfer in both animal models. While in MPS VI cats close to normal levels of serum ARSB have been reached and maintained for up to 1 year after gene transfer, lower and transient levels of circulating enzyme were detected in AAV- treated MPS VI rats, despite high ARSB levels in the transduced tissues. Consequently, the rescue of biochemical, morphological, and functional abnormalities in treated MPS VI rats has been partial. We are currently evaluating the presence of a humoral response to ARSB in AAV-treated MPS VI rats and whether this can be avoided by AAV-mediated transfer of the same species transgene.The results of our studies involving Arsb gene transfer in MPS VI animal models caused by different Arsb mutations may help to predict the outcome of ARSB gene transfer in humans.