title: Neonatal gene therapy with a gamma retroviral vector in mucopolysaccharidosis VI cats.
abstract: Mucopolysaccharidosis (MPS) VI is due to a deficiency in the activity of N-acetylgalactosamine 4-sulfatase (4S), also known as arylsulfatase B. Previously, retroviral vector (RV)-mediated neonatal gene therapy reduced the clinical manifestations of MPS I and MPS VII in mice and dogs. However, sulfatases require post-translational modification by sulfatase-modifying factors. MPS VI cats were injected intravenously (i.v.) with a gamma RV-expressing feline 4S, resulting in 5 ± 3 copies of RV per 100 cells in liver. Liver and serum 4S activity were 1,450 ± 1,720 U/mg (26-fold normal) and 107 ± 60 U/ml (13-fold normal), respectively, and were directly proportional to the liver 4S protein levels for individual cats. This study suggests that sulfatase-modifying factor (SUMF) activity in liver was sufficient to result in active enzyme despite overexpression of 4S. RV-treated MPS VI cats achieved higher body weights and longer appendicular skeleton lengths, had reduced articular cartilage erosion, and reduced aortic valve thickening and aortic dilatation compared with untreated MPS VI cats, although cervical vertebral bone lengths were not improved. This demonstrates that therapeutic expression of a functional sulfatase protein can be achieved with neonatal gene therapy using a gamma RV, but some aspects of bone disease remain difficult to treat.
authors.affiliation: Department of Internal Medicine, Washington University School of Medicine, St Louis, Missouri 63110, USA. kponder@dom.wustl.edu
authors.forename: Katherine P
authors.initials: KP
authors.lastname: Ponder
authors.forename: Thomas M
authors.initials: TM
authors.lastname: O'Malley
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.forename: Patricia A
authors.initials: PA
authors.lastname: O'Donnell
authors.forename: Anne M
authors.initials: AM
authors.lastname: Traas
authors.forename: Van W
authors.initials: VW
authors.lastname: Knox
authors.forename: Gustavo A
authors.initials: GA
authors.lastname: Aguirre
authors.forename: N Matthew
authors.initials: NM
authors.lastname: Ellinwood
authors.forename: Jason A
authors.initials: JA
authors.lastname: Metcalf
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.forename: Emma J
authors.initials: EJ
authors.lastname: Parkinson-Lawrence
authors.forename: Meg M
authors.initials: MM
authors.lastname: Sleeper
authors.forename: Doug A
authors.initials: DA
authors.lastname: Brooks
authors.forename: John J
authors.initials: JJ
authors.lastname: Hopwood
authors.forename: Mark E
authors.initials: ME
authors.lastname: Haskins
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001835:Body Weight; D002371:Cat Diseases / Q000201:enzymology / Q000235:genetics / Q000628:therapy*; D002415:Cats; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors; D007275:Injections, Intravenous; D008297:Male; D008979:Moloney murine leukemia virus / Q000235:genetics*; D009087:Mucopolysaccharidosis VI / Q000201:enzymology / Q000235:genetics / Q000628:therapy / Q000662:veterinary*; D020051:N-Acetylgalactosamine-4-Sulfatase / Q000235:genetics* / Q000378:metabolism; D011499:Protein Processing, Post-Translational
chemical_list: D020051:N-Acetylgalactosamine-4-Sulfatase