In vivo selection of hepatocytes transduced with adeno-associated viral vectors.
A murine model for hereditary tyrosinemia Type I (HTI) was evaluated for in vivo gene therapy with adeno-associated viral (AAV) vectors expressing the enzyme fumarylacetoacetate hydrolase. Transduction of a limited number of hepatocytes was accomplished following infusion of vector into the portal circulation. Corrected hepatocytes were expanded in vivo by withdrawing a drug which prevents the accumulation of toxic metabolites. The liver was eventually repopulated with hepatocytes harboring a functional and apparently integrated AAV provirus. Recipient animals regained normal liver function and architecture and the underlying metabolic derangements were normalized. After 9 months, vector-treated animals showed benign hepatomas, whereas in untreated animals areas of marked dysplasia were present within hepatomas.
Institute for Human Gene Therapy, Department of Molecular and Cellular Engineering, University of Pennsylvania, Philadelphia, PA 19104, USA.
S J
SJ
Chen
J
J
Tazelaar
A D
AD
Moscioni
J M
JM
Wilson
D000818:Animals; D015153:Blotting, Western; D001973:Bromodeoxyuridine / Q000378:metabolism; D002478:Cells, Cultured; D003510:Cyclohexanes / Q000494:pharmacology; D000229:Dependovirus / Q000201:enzymology / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression; D015316:Genetic Therapy; D005822:Genetic Vectors; D006867:Hydrolases / Q000096:biosynthesis* / Q000235:genetics; D007150:Immunohistochemistry; D008099:Liver / Q000201:enzymology* / Q000473:pathology / Q000821:virology; D008114:Liver Neoplasms, Experimental / Q000209:etiology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D014162:Transfection; D020176:Tyrosinemias / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000628:therapy*
D003510:Cyclohexanes; D006867:Hydrolases; C020156:fumarylacetoacetase; D001973:Bromodeoxyuridine