TY - JOUR
T1 - Long-term amelioration of feline mucopolysaccharidosis VI after AAV-mediated liver gene transfer
AU - Cotugno, Gabriella
AU - Annunziata, Patrizia
AU - Tessitore, Alessandra
AU - O'Malley, Thomas
AU - Capalbo, Anita
AU - Faella, Armida
AU - Bartolomeo, Rosa
AU - O'Donnell, Patricia
AU - Wang, Ping
AU - Russo, Fabio
AU - Sleeper, Meg M.
AU - Knox, Van W.
AU - Fernandez, Steven
AU - Levanduski, Leah
AU - Hopwood, John
AU - De Leonibus, Elvira
AU - Haskins, Mark
AU - Auricchio, Alberto
PY - 2011/3
Y1 - 2011/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=79952190655&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79952190655&partnerID=8YFLogxK
U2 - 10.1038/mt.2010.257
DO - 10.1038/mt.2010.257
M3 - Article
C2 - 21119624
AN - SCOPUS:79952190655
VL - 19
SP - 461
EP - 469
JO - Molecular Therapy
JF - Molecular Therapy
SN - 1525-0016
IS - 3
ER -