title: Targeted gene transfer into ependymal cells through intraventricular injection of AAV1 vector and long-term enzyme replacement via the CSF.
abstract: Enzyme replacement via the cerebrospinal fluid (CSF) has been shown to ameliorate neurological symptoms in model animals with neuropathic metabolic disorders. Gene therapy via the CSF offers a means to achieve a long-term sustainable supply of therapeutic proteins within the central nervous system (CNS) by setting up a continuous source of transgenic products. In the present study, a serotype 1 adeno-associated virus (AAV1) vector was injected into a lateral cerebral ventricle in adult mice to transduce the gene encoding human lysosomal enzyme arylsulfatase A (hASA) into the cells of the CNS. Widespread transduction and stable expression of hASA in the choroid plexus and ependymal cells was observed throughout the ventricles for more than 1 year after vector injection. Although humoral immunity to hASA developed after 6 weeks, which diminished the hASA levels detected in CSF from AAV1-injected mice, hASA levels in CSF were maintained for at least 12 weeks when the mice were tolerized to hASA prior of vector injection. Our results suggest that the cells lining the ventricles could potentially serve as a biological reservoir for long-term continuous secretion of lysosomal enzymes into the CSF following intracerebroventricular injection of an AAV1 vector.
authors: Department of Biochemistry and Molecular Biology, Division of Gene Therapy Research Center for Advanced Medical Technology, Nippon Medical School, Bunkyo-ku, Tokyo, Japan.
authors: Yoshiyuki
authors: Y
authors: Yamazaki
authors: Department of Biochemistry and Molecular Biology, Division of Gene Therapy Research Center for Advanced Medical Technology, Nippon Medical School, Bunkyo-ku, Tokyo, Japan.
authors: Yukihiko
authors: Y
authors: Hirai
authors: Department of Biochemistry and Molecular Biology, Division of Gene Therapy Research Center for Advanced Medical Technology, Nippon Medical School, Bunkyo-ku, Tokyo, Japan.
authors: Koichi
authors: K
authors: Miyake
authors: Department of Biochemistry and Molecular Biology, Division of Gene Therapy Research Center for Advanced Medical Technology, Nippon Medical School, Bunkyo-ku, Tokyo, Japan.
authors: Takashi
authors: T
authors: Shimada
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D002553:Cerebroside-Sulfatase / Q000134:cerebrospinal fluid* / Q000235:genetics*; D004805:Ependyma / Q000166:cytology / Q000502:physiology*; D018390:Gene Targeting / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics*; D007276:Injections, Intraventricular; D008137:Longitudinal Studies; D051379:Mice; D008810:Mice, Inbred C57BL; D014162:Transfection / Q000379:methods
chemical_list: D002553:Cerebroside-Sulfatase