Increased susceptibility to the pathogenic effects of wild-type and recombinant herpesviruses in MPS VII mice compared to normal siblings

Journal of Neurovirology
J H WolfeN W Fraser

Abstract

In previous studies, we have shown that a herpesvirus vector can transfer a therapeutic cellular gene (beta-glucuronidase) from peripheral sites of inoculation into the central nervous system in mice with a model neurodegenerative disease caused by a deficiency of this enzyme (mucopolysaccharidosis type VII, Sly disease). The vector corrects the enzymatic deficiency in transduced cells but the number of cells corrected is too low to alter the pathology of the disease. The recombinant vector virus, which has the foreign gene substituted into the viral LAT locus, had reduced pathogenicity after corneal inoculation compared to the wild-type virus from which it was derived (HSV-1 strain 17+). We therefore attempted to increase the number of corrected cells in the MPS VII brain by increasing the inoculating dose of the vector. However, the vector was acutely pathogenic in the diseased mice at doses that were non-pathogenic in normal littermates. The pathogenic effect of the vector virus in the mutants could be blocked by passive immunization with human gamma-globulin containing anti-HSV-1 antibodies on the day of infection but not when given at the peak of viral replication (day 4). However, effective protection also blocked transdu...Continue Reading

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