Liver, Pancreas, and Biliary TractA replication-deficient rSV40 mediates liver-directed gene transfer and a long-term amelioration of jaundice in Gunn rats☆,☆☆
Section snippets
Animals
Inbred Gunn rats of both sexes (200–300 g body wt) were obtained from our colony in the Special Animal Core of the Marion Bessin Liver Center of the Albert Einstein College of Medicine. The rats were maintained on standard laboratory chow and kept in 12-hour light/dark cycles. All experiments were performed under an Institutional Animal Care and Use Committee–approved protocol.
Generation of the replication-deficient recombinant SV40-hBUGT virus
The generation and structure of the pSV5 have been described previously.21 Briefly, this plasmid contains an SV40
Infectious titer
Infectious titers of SV-hBUGT were determined by in situ PCR after infection of a monkey kidney cell line, TC7, with serial dilutions of virus preparation. Virus yields ranged from 5 × 109 to 1 × 1010 infectious units (IU)/mL.
Evaluation of gene transfer and transgene expression
Liver biopsies were performed 2 and 6 weeks after administration of a single injection or 3 daily injections of 3 × 109 IU of SV-hBUGT into the portal vein. As a control for these studies we used SVLuc, in which firefly luciferase was substituted for SV40 Tag.20 The biopsy
Discussion
CN-1 is a life-threatening disease in which a lack of bilirubin UGT activity causes bilirubin encephalopathy. Despite the routine use of phototherapy and intermittent plasmapheresis, patients with CN-1 are at life-long risk of kernicterus. Liver transplantation cures the metabolic abnormality. However, this procedure is expensive, is not without risk, and necessitates life-long immunosuppression. Because CN-1 is caused by deficiency of a single enzyme activity, and the liver is otherwise
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Generation of a Vero-Based Packaging Cell Line to Produce SV40 Gene Delivery Vectors for Use in Clinical Gene Therapy Studies
2017, Molecular Therapy Methods and Clinical DevelopmentCitation Excerpt :RD SV40 vectors have been generated by deleting the coding region of the two early non-structural proteins named large T antigen (LTag) and small T antigen (STag), giving 2.7 kb of space for cloning the transgene encoding the therapeutic protein or RNA. SV40 vectors transduce a wide range of cell types in vivo, and their therapeutic potential has been demonstrated in animal models of human disease.22–26 Because humans can be considered naive to SV40,27,28 it is expected that RD SV40 vectors are non-immunogenic or tolerogenic when applied in clinical settings.
Bilirubin Metabolism and Its Disorders
2017, Zakim and Boyer's Hepatology: A Textbook of Liver DiseaseBilirubin Metabolism and its Disorders
2012, Zakim and Boyer's Hepatology
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Address requests for reprints to: David S. Strayer, M.D., Department of Pathology, Jefferson Medical College, 1020 Locust Street, Philadelphia, Pennsylvania 19107. e-mail: [email protected]; fax: (215) 503-1156.
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Supported in part by grants DK 46057 (to J.R.C.), DK 34357 (to N.R.C.), and AI41399 and RR13156 (to D.S.S.) from the National Institutes of Health; by Liver Research Core Center grant P30-DK 41296 (Director, D. A. Shafritz); and by the Gene Therapy Core of the Seaver Institute of Human Genetics of the Albert Einstein College of Medicine. B.V.S. was supported by a grant from the Swiss National Science Foundation.