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.
Chen
S J
SJ
Institute for Human Gene Therapy, Department of Molecular and Cellular Engineering, University of Pennsylvania, Philadelphia, PA 19104, USA.
Tazelaar
J
J
Moscioni
A D
AD
Wilson
J M
JM
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