title: Liver-directed gene therapy corrects cardiovascular lesions in feline mucopolysaccharidosis type I.
abstract: Patients with mucopolysaccharidosis type I (MPS I), a genetic deficiency of the lysosomal enzyme α-l-iduronidase (IDUA), exhibit accumulation of glycosaminoglycans in tissues, with resulting diverse clinical manifestations including neurological, ocular, skeletal, and cardiac disease. MPS I is currently treated with hematopoietic stem cell transplantation or weekly enzyme infusions, but these therapies have significant drawbacks for patient safety and quality of life and do not effectively address some of the most critical clinical sequelae, such as life-threatening cardiac valve involvement. Using the naturally occurring feline model of MPS I, we tested liver-directed gene therapy as a means of achieving long-term systemic IDUA reconstitution. We treated four MPS I cats at 3-5 mo of age with an adeno-associated virus serotype 8 vector expressing feline IDUA from a liver-specific promoter. We observed sustained serum enzyme activity for 6 mo at ∼ 30% of normal levels in one animal, and in excess of normal levels in three animals. Remarkably, treated animals not only demonstrated reductions in glycosaminoglycan storage in most tissues, but most also exhibited complete resolution of aortic valve lesions, an effect that has not been previously observed in this animal model or in MPS I patients treated with current therapies. These data point to clinically meaningful benefits of the robust enzyme expression achieved with hepatic gene transfer that extend beyond the economic and quality of life advantages over lifelong enzyme infusions.
authors.affiliation: Gene Therapy Program, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, and.
authors.forename: Christian
authors.initials: C
authors.lastname: Hinderer
authors.affiliation: Gene Therapy Program, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, and.
authors.forename: Peter
authors.initials: P
authors.lastname: Bell
authors.affiliation: Gene Therapy Program, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, and.
authors.forename: Brittney L
authors.initials: BL
authors.lastname: Gurda
authors.affiliation: Gene Therapy Program, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, and.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Section of Anatomy, Department of Basic Medical Sciences, Mona Campus, University of the West Indies, Kingston, Jamaica.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Louboutin
authors.affiliation: Gene Therapy Program, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, and.
authors.forename: Yanqing
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Departments of Pathobiology and Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104; and.
authors.forename: Jessica
authors.initials: J
authors.lastname: Bagel
authors.affiliation: Departments of Pathobiology and Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104; and.
authors.forename: Patricia
authors.initials: P
authors.lastname: O'Donnell
authors.affiliation: Departments of Pathobiology and Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104; and.
authors.forename: Tracey
authors.initials: T
authors.lastname: Sikora
authors.affiliation: Departments of Pathobiology and Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104; and.
authors.forename: Therese
authors.initials: T
authors.lastname: Ruane
authors.affiliation: Departments of Pathobiology and Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104; and.
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.affiliation: Departments of Pathobiology and Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104; and.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Haskins
authors.affiliation: Gene Therapy Program, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, and wilsonjm@mail.med.upenn.edu.
authors.forename: James M
authors.initials: JM
authors.lastname: Wilson
mesh_terms: D000818:Animals; D001021:Aortic Valve / Q000378:metabolism / Q000473:pathology; D002318:Cardiovascular Diseases / Q000473:pathology / Q000628:therapy*; D002415:Cats; D000229:Dependovirus / Q000235:genetics; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000378:metabolism; D006025:Glycosaminoglycans / Q000378:metabolism; D015844:Heparin Cofactor II / Q000378:metabolism; D007068:Iduronidase / Q000097:blood / Q000235:genetics / Q000627:therapeutic use; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008969:Molecular Sequence Data; D008059:Mucopolysaccharidosis I / Q000097:blood / Q000473:pathology / Q000628:therapy*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D013917:Thrombin / Q000378:metabolism; D014018:Tissue Distribution; D014161:Transduction, Genetic
chemical_list: D006025:Glycosaminoglycans; D015844:Heparin Cofactor II; D007068:Iduronidase; D013917:Thrombin
keywords: AAV; lysosomal storage disease