Report Summary

Effect of HCV Infection in Safety and Efficacy of Liver Delivery of rAAV-AAT

Study Summary

Overall Study Design 
Aim 1 To determine whether the presence of chronic Hepatitis C virus HCV infection in a nonhuman primate 
chimpanzee model will increase the risk of acute toxicity from portal vein administration of recombinant Adeno-Associated 
Virus Serotype 2-chimpanzee-alpha-1 Antitrypsin rAAV2-CB-chAAT gene vector 
Aim 2 To determine whether the presence of chronic HCV infection will alter the persistence of rAAV2-CB-chAAT-vector 
DNA within the liver 
Aim 3 To evaluate and observe rAAV2-CB-chAAT-treated with HCV-positive chimpanzees for any evidence of germ-line 
transmission Outside of this protocol these chimps will be monitored long-term for hepatic carcinogenesis 
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 pre-existing HCV infection Doses of approximately 1x10e13 vector genomes of a rAAV2-chimpanzee alpha-1 
antitrypsin rAAV2-cAAT vector were injected into the portal veins of each of 3 HCV-genome chimpanzees and 3 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 both the pre-treatment 5 
days prior liver biopsy and after the vector injection However HCV animals demonstrated a substantially greater rise in 
AST ALT and CPK values than HCV- animals Histopathology demonstrated abnormal lipid accumulation steatosis in 
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 
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