X-Message-Number: 2479
From:  (David Stodolsky)
Subject: CRYONICS: Bloodbrain barrier, etc.
Date: Tue, 7 Dec 93 00:17:52 +0100 

> Date: Thu, 2 Dec 93 17:29:01 EST
> From: "Stevan Harnad" <>
> To: 
> Subject: Neural Transplantation: BBS Call for Commentators
> [...]

3.
        GENE REPLACEMENT THERAPY IN THE CENTRAL NERVOUS SYSTEM:
    VIRAL VECTOR MEDIATED THERAPY OF GLOBAL NEURODEGENERATIVE DISEASE

        Edward A.Neuwelt, Michael A. Pagel, Leslie L. Muldoon
                Oregon Health Sciences University,
                Portland OR 97201

                Alred Geller
                Children's Hospital
                Boston, MA 02115

KEYWORDS: adenovirus; blood-brain barrier; gene therapy; herpes
virus; pHexosaminidase

ABSTRACT: This target article describes the current state of global
gene replacement in the brain through the use of viral vectors and it
assesses possible solutions to some of the many problems inherent in
gene therapy for the central nervous system (CNS). Gene replacement
therapy is a way to generate normal human proteins in deficient cells,
making cures possible for certain genetically inherited enzyme
deficiences, metabolic diseases, and cancers. The two major issues to
be addressed are the delivery of genetic material to the brain and the
expression of recombinant genetic material in CNS target cells. Focal
inoculation of recombinant virions or other genetic vectors has
limitations when there is global brain disease. A new
blood-brain-barrier (BBB) disruption technique, in which hypertonic
mannitol transiently shrinks the BBB endothelium, allows the passage of
high molecular weight compounds and even viruses. CNS gene therapy will
require a viral vector system that allows long-term, nontoxic gene
expression in neurons or glial cells. Retroviral vectors have
limitations in CNS gene replacement, although they are suitable for
expressing recombinant genes in intracerebral grafts, or toxic genes in
brain tumors. Mutant neurotropic viruses with reduced neurotoxicity
(e.g., defective herpes simplex virus type 1 [HSV-1], the HSV-1
amplicon vector system we have developed, or adenovirus mutants) have
potential for direct treatment of neurons. Injecting these vectors into
rodent brains can lead to the stable expression of foreign genetic
material in postmitotic neuronal cells. We discuss our BBB disruption
delivery technique, our defective HSV-1 aplicon vector system, and our
feline model for the neuronal lysosomal storage disorder
Gm2-gangliosidosis (Sandhoff disease), which may prove to be a useful
model system for CNS gene therapy.
----------------------------------------------------------------------
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David S. Stodolsky              Internet: 
Peder Lykkes Vej 8, 4 tv.                         
DK-2300 Copenhagen S                          Tel.: + 45 31 59 76 44
Denmark                                        Fax: + 45 35 32 33 99

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