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- Title
Long-term Amelioration of Feline Mucopolysaccharidosis VI After AAV-mediated Liver Gene Transfer.
- Authors
Cotugno, Gabriella; Annunziata, Patrizia; Tessitore, Alessandra; O'Malley, Thomas; Capalbo, Anita; Faella, Armida; Bartolomeo, Rosa; O'Donnell, Patricia; Ping Wang; Russo, Fabio; Sleeper, Meg M.; Knox, Van W.; Fernandez, Steven; Levanduski, Leah; Hopwood, John; De Leonibus, Elvira; Haskins, Mark; Auricchio, Alberto
- Abstract
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.
- Subjects
GENE therapy; CELLULAR therapy; MUCOPOLYSACCHARIDOSIS; ARYLSULFATASES; LYSOSOMAL storage diseases; GLYCOSAMINOGLYCANS; GENETIC transformation
- Publication
Molecular Therapy, 2011, Vol 19, Issue 3, p461
- ISSN
1525-0016
- Publication type
Article
- DOI
10.1038/mt.2010.257