title: Delivery of an Adeno-Associated Virus Vector into Cerebrospinal Fluid Attenuates Central Nervous System Disease in Mucopolysaccharidosis Type II Mice.
abstract: Mucopolysaccharidosis type II (MPS II) is a rare X-linked genetic disorder caused by deficiency of the lysosomal enzyme iduronate-2-sulfatase (IDS), leading to impaired catabolism of ubiquitous polysaccharides and abnormal accumulation of these undegraded substrates in the lysosome. Like many lysosomal storage diseases, MPS II is characterized by both somatic and central nervous system (CNS) involvement. Intravenous enzyme replacement therapy can improve somatic manifestations of MPS II, but systemic IDS does not cross the blood-brain barrier and therefore cannot address CNS disease. In this study, an adeno-associated virus serotype 9 vector carrying the IDS gene was injected into the cerebrospinal fluid (CSF) of IDS deficient mice, a model of MPS II. Treated mice exhibited dose-dependent IDS expression and resolution of brain storage lesions, as well as improvement in long-term memory in a novel object recognition test. These findings suggest that delivery of adeno-associated virus vectors into CSF could serve as a platform for efficient, long-term enzyme delivery to the CNS, potentially addressing this critical unmet need for patients with MPS II and many related lysosomal enzyme deficiencies.
authors: 1 Gene Therapy Program, Department of Medicine, University of Pennsylvania , Philadelphia, Pennsylvania.
authors: Christian
authors: C
authors: Hinderer
authors: 1 Gene Therapy Program, Department of Medicine, University of Pennsylvania , Philadelphia, Pennsylvania.
authors: Nathan
authors: N
authors: Katz
authors: 2 Section of Anatomy, Department of Basic Medical Sciences, University of West Indies , Kingston, Jamaica.
authors: Jean-Pierre
authors: JP
authors: Louboutin
authors: 1 Gene Therapy Program, Department of Medicine, University of Pennsylvania , Philadelphia, Pennsylvania.
authors: Peter
authors: P
authors: Bell
authors: 1 Gene Therapy Program, Department of Medicine, University of Pennsylvania , Philadelphia, Pennsylvania.
authors: Hongwei
authors: H
authors: Yu
authors: 1 Gene Therapy Program, Department of Medicine, University of Pennsylvania , Philadelphia, Pennsylvania.
authors: Mohamad
authors: M
authors: Nayal
authors: 3 REGENXBIO , Rockville, Maryland.
authors: Karen
authors: K
authors: Kozarsky
authors: 4 Department of Neuroscience, University of Pennsylvania , Philadelphia, Pennsylvania.
authors: W Timothy
authors: WT
authors: O'Brien
authors: 1 Gene Therapy Program, Department of Medicine, University of Pennsylvania , Philadelphia, Pennsylvania.
authors: Tamara
authors: T
authors: Goode
authors: 1 Gene Therapy Program, Department of Medicine, University of Pennsylvania , Philadelphia, Pennsylvania.
authors: James M
authors: JM
authors: Wilson
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier; D002493:Central Nervous System Diseases / Q000235:genetics / Q000628:therapy*; D002555:Cerebrospinal Fluid / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics*; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D056947:Enzyme Replacement Therapy; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage*; D006023:Glycoproteins / Q000235:genetics*; D006801:Humans; D007068:Iduronidase / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016532:Mucopolysaccharidosis II / Q000134:cerebrospinal fluid / Q000503:physiopathology*
chemical_list: D006023:Glycoproteins; C018322:IDS protein, human; C000615655:IDUA protein, human; D007068:Iduronidase
keywords: AAV; MPS II; central nervous system; gene transfer; intrathecal; lysosomal storage disease