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
Publication Date
2008-07-01
Document Type
Article
Subjects
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.
DOI of Published Version
10.1089/hum.2007.174
Source
Hum Gene Ther. 2008 Jul;19(7):681-9. Link to article on publisher's site
Journal/Book/Conference Title
Human gene therapy
Related Resources
PubMed ID
18588426
Repository Citation
Flotte TR, Goetzmann J, Caridi J, Paolillo J, Conlon TJ, Potter M, Mueller C, Bryne BJ. (2008). Apparently nonspecific enzyme elevations after portal vein delivery of recombinant adeno-associated virus serotype 2 vector in hepatitis C virus-infected chimpanzees. Pulmonary and Allergy. https://doi.org/10.1089/hum.2007.174. Retrieved from https://escholarship.umassmed.edu/peds_pulmonary/25