Long-term Amelioration of Feline Mucopolysaccharidosis VI After AAV-mediated Liver Gene Transfer

• Published in: Molecular therapy 2011-03, Vol.19 (3), p.461-469
• Main Authors: Cotugno, Gabriella, Annunziata, Patrizia, Tessitore, Alessandra, O'Malley, Thomas, Capalbo, Anita, Faella, Armida, Bartolomeo, Rosa, O'Donnell, Patricia, Wang, Ping, Russo, Fabio, Sleeper, Meg M, Knox, Van W, Fernandez, Steven, Levanduski, Leah, Hopwood, John, De Leonibus, Elvira, Haskins, Mark, Auricchio, Alberto
• Format: Article
• Language: English
• Subjects: Adeno-associated virus; Animals; Bone and Bones - metabolism; Bone and Bones - pathology; Cats; Dependovirus - genetics; Drug dosages; Enzymes; Gene Expression Regulation - drug effects; Gene Expression Regulation - genetics; Gene therapy; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors - administration & dosage; Genetic Vectors - genetics; Genomes; Glycosaminoglycans - metabolism; HEK293 Cells; Humans; Liver; Liver - metabolism; Motor Activity - drug effects; Motor Activity - genetics; Mucopolysaccharidosis VI - enzymology; Mucopolysaccharidosis VI - pathology; Mucopolysaccharidosis VI - therapy; Mutation; N-Acetylgalactosamine-4-Sulfatase - genetics; N-Acetylgalactosamine-4-Sulfatase - metabolism; Original; Pathology; Phenotype; Treatment Outcome; Vectors (Biology); Veterinary colleges; Veterinary medicine
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1038/mt.2010.257

Mucopolysaccharidosis VI (MPS VI) is caused by deficient arylsulfatase B (ARSB) activity resulting in lysosomal storage of glycosaminoglycans (GAGs). MPS VI is characterized by dysostosis multiplex, organomegaly, corneal clouding, and heart valve thickening. Gene transfer to a factory organ like liver may provide a lifetime source of secreted ARSB. We show that intravascular administration of adeno-associated viral vectors (AAV) 2/8-TBG-felineARSB in MPS VI cats resulted in ARSB expression up to 1 year, the last time point of the study. In newborn cats, normal circulating ARSB activity was achieved following delivery of high vector doses (6 × 1013 genome copies (gc)/kg) whereas delivery of AAV2/8 vector doses as low as 2 × 1012 gc/kg resulted in higher than normal serum ARSB levels in juvenile MPS VI cats. In MPS VI cats showing high serum ARSB levels, independent of the age at treatment, we observed: (i) clearance of GAG storage, (ii) improvement of long bone length, (iii) reduction of heart valve thickness, and (iv) improvement in spontaneous mobility. Thus, AAV2/ 8-mediated liver gene transfer represents a promising therapeutic strategy for MPS VI patients.