title: Biochemical, pathological, and skeletal improvement of mucopolysaccharidosis VI after gene transfer to liver but not to muscle.
abstract: 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.
authors.affiliation: Telethon Institute of Genetics and Medicine, Naples, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Tessitore
authors.forename: Armida
authors.initials: A
authors.lastname: Faella
authors.forename: Thomas
authors.initials: T
authors.lastname: O'Malley
authors.forename: Gabriella
authors.initials: G
authors.lastname: Cotugno
authors.forename: Monica
authors.initials: M
authors.lastname: Doria
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Kunieda
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Matarese
authors.forename: Mark
authors.initials: M
authors.lastname: Haskins
authors.forename: Alberto
authors.initials: A
authors.lastname: Auricchio
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001842:Bone and Bones / Q000201:enzymology / Q000473:pathology*; D002415:Cats; D000229:Dependovirus / Q000235:genetics; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage; D008099:Liver / Q000201:enzymology*; D008297:Male; D009087:Mucopolysaccharidosis VI / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D018482:Muscle, Skeletal / Q000201:enzymology*; D020051:N-Acetylgalactosamine-4-Sulfatase / Q000008:administration & dosage* / Q000235:genetics*; D052097:Quadriceps Muscle / Q000201:enzymology; D051381:Rats
chemical_list: D020051:N-Acetylgalactosamine-4-Sulfatase