Apparently nonspecific enzyme elevations after portal vein delivery of recombinant adeno-associated virus serotype 2 vector in hepatitis C virus-infected chimpanzees
Authors
Flotte, Terence R.Goetzmann, Jason
Caridi, James
Paolillo, Joseph
Conlon, Thomas J.
Potter, Mark
Mueller, Christian
Bryne, Barry J.
Document Type
Journal ArticlePublication Date
2008-07-01Keywords
Alanine TransaminaseAnimals
Antibodies
Antibodies, Viral
Aspartate Aminotransferases
Creatinine
Dependovirus
Fatty Liver
*Genetic Vectors
Hepatitis C
Injections, Intravenous
*Liver
Pan troglodytes
Phosphotransferases
*Portal Vein
*Recombination, Genetic
Serotyping
Treatment Outcome
Up-Regulation
alpha 1-Antitrypsin
Allergy and Immunology
Genetics and Genomics
Pediatrics
Metadata
Show full item recordAbstract
Hepatic gene transfer is envisioned as a substitute for protein replacement therapies, many of which are derived from blood products. Thus, the target populations may have a high prevalence of blood-borne pathogens, such as hepatitis C virus (HCV). We sought to determine whether the safety of recombinant adeno-associated virus serotype 2 (rAAV2) would be altered by preexisting HCV infection. Doses of approximately 1 x 10(13) vector genomes of an rAAV2-chimpanzee alpha(1)-antitrypsin (rAAV2-cAAT) vector were injected into the portal vein of each of three HCV genome-positive (HCV+) chimpanzees and three HCV-negative (HCV-) controls. Acute safety studies were performed up to 90 days after vector administration, along with analyses of the peripheral blood and liver tissue for rAAV2-cAAT genomes. Vector genome copy numbers in blood and liver tissue were similar in both groups. All animals demonstrated increases in liver and muscle enzyme levels after the pretreatment liver biopsy (5 days before vector injection) and after the vector injection. However, HCV+ animals demonstrated a substantially greater rise in aspartate aminotransferase, alanine aminotransferase, and creatinine phosphokinase values than HCV- animals. Histopathology demonstrated abnormal lipid accumulation (steatosis) in the hepatocytes of HCV+ animals, both before and after vector injection. These data indicate an increased susceptibility to subclinical liver toxicity from portal vein injection of rAAV2 in the presence of HCV infection.Source
Hum Gene Ther. 2008 Jul;19(7):681-9. Link to article on publisher's siteDOI
10.1089/hum.2007.174Permanent Link to this Item
http://hdl.handle.net/20.500.14038/43810PubMed ID
18588426Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1089/hum.2007.174