Apparently nonspecific enzyme elevations after portal vein delivery of recombinant adeno-associated virus serotype 2 vector in hepatitis C virus-infected chimpanzees.
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.
Flotte
Terence R
TR
Department of Pediatrics, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Goetzmann
Jason
J
Caridi
James
J
Paolillo
Joseph
J
Conlon
Thomas J
TJ
Potter
Mark
M
Mueller
Christian
C
Byrne
Barry J
BJ
D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D000906:Antibodies / Q000097:blood; D000914:Antibodies, Viral / Q000097:blood; D001219:Aspartate Aminotransferases / Q000378:metabolism; D003404:Creatinine / Q000378:metabolism; D000229:Dependovirus / Q000145:classification / Q000235:genetics* / Q000276:immunology; D005234:Fatty Liver / Q000473:pathology; D005822:Genetic Vectors / Q000008:administration & dosage / Q000009:adverse effects; D006526:Hepatitis C / Q000473:pathology / Q000821:virology; D007275:Injections, Intravenous; D008099:Liver / Q000201:enzymology / Q000473:pathology / Q000821:virology; D002679:Pan troglodytes; D010770:Phosphotransferases / Q000378:metabolism; D011169:Portal Vein; D011995:Recombination, Genetic; D012703:Serotyping; D016896:Treatment Outcome; D015854:Up-Regulation; D000515:alpha 1-Antitrypsin / Q000235:genetics* / Q000276:immunology / Q000378:metabolism
D000906:Antibodies; D000914:Antibodies, Viral; D000515:alpha 1-Antitrypsin; D003404:Creatinine; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D010770:Phosphotransferases