Elsevier

Experimental Neurology

Volume 160, Issue 1, November 1999, Pages 109-116
Experimental Neurology

Regular Article
Systemic Hyperosmolality Improves β-Glucuronidase Distribution and Pathology in Murine MPS VII Brain Following Intraventricular Gene Transfer

https://doi.org/10.1006/exnr.1999.7205Get rights and content

Abstract

Mucopolysaccharidosis VII, a classical lysosomal storage disease, is caused by deficiency of the enzyme β-glucuronidase. Central nervous system (CNS) manifestations are severe with accumulations of storage vacuoles in all cell types. Intraventricular gene transfer can lead to transduction of the ependyma, with production and secretion of β-glucuronidase into the cerebral spinal fluid and underlying cortex resulting in reversal of disease pathology restricted to the periventricular areas. We tested if systemic hyperosmolality would increase the distribution of β-glucuronidase in brain parenchyma after intraventricular virus injection. Mice were administered mannitol, intraperitoneally, 20 days after gene transfer and 1 day prior to sacrifice. Mannitol-induced systemic hyperosmolality caused a marked penetration of β-glucuronidase into the brain parenchyma. If mannitol was administered at the time of the intraventricular injection of virus, there was penetration of vector across the ependymal cell layer, with infection of cells in the subependymal region. This also resulted in increased β-glucuronidase activity throughout the brain. Sections of brains from β-glucuronidase-deficient mice showed correction of cellular pathology in the subependymal region plus cortical structures away from the ventricular wall. These data indicate that virus-mediated gene transfer to the brain via the ventricles, coupled with systemic mannitol administration, can lead to extensive CNS distribution of β-glucuronidase with concomitant correction of the storage defect. Our findings have positive therapeutic implications for the treatment of CNS disorders with gene transfer vectors and recombinant proteins.

References (51)

  • V. Biousse et al.

    Visual fields in patients with posterior GPi pallidotomy

    Neurology

    (1998)
  • E.H. Birkenmeier

    Correction of murine mucopolysaccharidosis type VII (MPS VII) by bone marrow transplantation and gene transfer therapy

    Hum. Gene Ther.

    (1991)
  • E.H. Birkenmeier et al.

    Murine mucopolysaccharidosis type VII. Characterization of a mouse with beta-glucuronidase deficiency

    J. Clin. Invest.

    (1989)
  • M.W. Brightman et al.

    Junctions between intimately apposed cell membranes in the vertebrate brain

    J. Cell Biol.

    (1969)
  • H.F. Cserr et al.

    Efflux of radiolabeled polyethylene glycols and albumin from rat brain

    Am. J. Physiol.

    (1981)
  • H.F. Cserr et al.

    Regulation of brain water and electrolytes during acute hyperosmolality in rats

    Am. J. Physiol.

    (1987)
  • H.F. Cserr et al.

    Convection of cerebral interstitial fluid and its role in brain volume regulation

    Ann. NY Acad. Sci.

    (1986)
  • H.F. Cserr et al.

    Bulk flow of interstitial fluid after intracranial injection of Blue Dextran 2000

    Exp. Neurol.

    (1974)
  • M.R. Del Bigio

    The ependyma: A protective barrier between brain and cerebrospinal fluid

    Glia

    (1995)
  • T. Donato et al.

    Effect of Mannitol on Cerebrospinal Fluid Dynamics and Brain Tissue Edema

    Anesth. Analg.

    (1994)
  • S.E. Doran et al.

    Gene expression from recombinant viral vectors in the central nervous system after blood-brain barrier disruption

    Neurosurgery

    (1995)
  • M.J. During et al.

    Intraventricular delivery of gene therapy in the fetal pediatric neurogenetic disorder, Canavan's disease

    Am. Assoc. Neurol. Surg.

    (1998)
  • A. Ghodsi et al.

    Extensive β-glucuronidase activity in murine CNS after adenovirus mediated gene transfer to brain

    Hum. Gene Ther.

    (1998)
  • W. His

    Über ein perivasculäres Canalsystem in den nervösen Centralorganen and über dessen Beziehungen zum Lymphsystem

    Z. Wiss. Zool.

    (1865)
  • T. Li et al.

    In vivo transfer of a reporter gene to the retina mediated by an adenoviral vector

    Invest. Ophthalmol. Vis. Sci.

    (1994)
  • Cited by (0)

    1

    To whom correspondence should be addressed at *Beverly L. Davidson, Ph.D. 200 EMRB, University of Iowa College of Medicine, Iowa City, IA 52242. Fax: (319) 353-5572. E-mail: beverly-davidson@ uiowa.edu.

    View full text