TY - JOUR
T1 - Biochemical, pathological, and skeletal improvement of mucopolysaccharidosis VI after gene transfer to liver but not to muscle
AU - Tessitore, Alessandra
AU - Faella, Armida
AU - O'Malley, Thomas
AU - Cotugno, Gabriella
AU - Doria, Monica
AU - Kunieda, Tetsuo
AU - Matarese, Giuseppe
AU - Haskins, Mark
AU - Auricchio, Alberto
N1 - Funding Information:
We thank Patricia O’Donnell and Karyn Cullen (School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA) for helping with the cat colony, Maurizio Di Tommaso for [Telethon Institute of Genetics and Medicine, (TIGEM)] technical support with the rat colony and the TIGEM Bioinformatics (Santosh Anand) and AAV Vector Cores. This work was supported by the Telethon Grant TIGEM P33, the EC-FP6-projects LSHB-CT-2005-512146 DiMI and 018933 Clinigene from the European Community, the grant D.M.589/7303/04 from the Italian Ministry of Agriculture, the National Institutes of Health grants DK25759 and RR02512 and the grant PRIN 2006064337 from the Italian Ministry of University and Research.
PY - 2008/1
Y1 - 2008/1
N2 - Mucopolysaccharidosis VI (MPS VI) is caused by deficient activity of arylsulfatase B (ARSB), resulting in intralysosomal storage of dermatan sulfate (DS) and multisystem disease without central nervous system involvement. After gene transfer, muscle or liver can theoretically be converted into factories for systemic ARSB secretion, leading to uptake by non-transduced cells. We have injected newborn MPS VI rats and cats with adeno-associated viral (AAV) vectors expressing ARSB under the control of liver-specific, muscle-specific, or universally active promoters. After systemic or intramuscular (IM) administration of AAV, therapeutic levels of circulating ARSB are achieved, resulting in skeletal improvements and significant decrease in glycosaminoglycan (GAG) storage, inflammation and apoptosis (despite a neutralizing immune response to ARSB in MPS VI rats). In addition, we have observed wide-spread dissemination of vector after IM AAV administration. This results in secretion of therapeutic levels of ARSB when the universally active cytomegalovirus (CMV) but not the muscle-specific muscle creatine kinase (MCK) promoter is used, suggesting that transduction of extramuscular sites rather than enzyme secretion from muscle occurs after muscle ARSB gene transfer. We conclude that AAV-mediated expression of ARSB from liver represents a feasible therapeutic strategy for MPS VI, potentially avoiding multiple infusions of costly recombinant enzyme associated with enzyme replacement therapy.
AB - Mucopolysaccharidosis VI (MPS VI) is caused by deficient activity of arylsulfatase B (ARSB), resulting in intralysosomal storage of dermatan sulfate (DS) and multisystem disease without central nervous system involvement. After gene transfer, muscle or liver can theoretically be converted into factories for systemic ARSB secretion, leading to uptake by non-transduced cells. We have injected newborn MPS VI rats and cats with adeno-associated viral (AAV) vectors expressing ARSB under the control of liver-specific, muscle-specific, or universally active promoters. After systemic or intramuscular (IM) administration of AAV, therapeutic levels of circulating ARSB are achieved, resulting in skeletal improvements and significant decrease in glycosaminoglycan (GAG) storage, inflammation and apoptosis (despite a neutralizing immune response to ARSB in MPS VI rats). In addition, we have observed wide-spread dissemination of vector after IM AAV administration. This results in secretion of therapeutic levels of ARSB when the universally active cytomegalovirus (CMV) but not the muscle-specific muscle creatine kinase (MCK) promoter is used, suggesting that transduction of extramuscular sites rather than enzyme secretion from muscle occurs after muscle ARSB gene transfer. We conclude that AAV-mediated expression of ARSB from liver represents a feasible therapeutic strategy for MPS VI, potentially avoiding multiple infusions of costly recombinant enzyme associated with enzyme replacement therapy.
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U2 - 10.1038/sj.mt.6300325
DO - 10.1038/sj.mt.6300325
M3 - Article
C2 - 17955027
AN - SCOPUS:37549000936
VL - 16
SP - 30
EP - 37
JO - Molecular Therapy
JF - Molecular Therapy
SN - 1525-0016
IS - 1
ER -