Title

Apparently nonspecific enzyme elevations after portal vein delivery of recombinant adeno-associated virus serotype 2 vector in hepatitis C virus-infected chimpanzees

UMMS Affiliation

Gene Therapy Center; Department of Pediatrics

Date

7-1-2008

Document Type

Article

Medical Subject Headings

Alanine Transaminase; Animals; 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

Disciplines

Allergy and Immunology | Genetics and Genomics | Pediatrics

Abstract

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.

Rights and Permissions

Citation: Hum Gene Ther. 2008 Jul;19(7):681-9. Link to article on publisher's site

Related Resources

Link to Article in PubMed

PubMed ID

18588426