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Author: Hojun Li, University of Pennsylvania
School of Medicine, Class of 2012
Hemophilia B is a severe bleeding disorder affecting 1 in 10,000
males. Gene therapy for Hemophilia B is a promising alternative to
recombinant protein therapy. Long-term expression of coagulation
factor IX (FIX) via stable gene transfer could reduce costs and
risks associated with intravenous recombinant FIX infusions. In a
human clinical trial (Manno, Nat Med 2006), our group has
previously shown hepatic artery injection of an adenoassociated
virus (AAV) vector expressing FIX (AAV-hFIX16) results in
short-term efficacy and disease correction. A fundamental issue
facing clinical gene transfer has to do with risk related to vector
integration into the host genome. The consequences of AAV
integration in in vivo systems is unknown. Here we present the
results of a large-scale prospective study to determine whether
integrated AAV vectors dysregulate nearby genes and increase cancer
We performed a large-scale longitudinal study following 120
wild-type mice for 18 months after portal vein injection of either
5e12 vg/kg of AAV-hFIX16, 1e14 vg/kg of AAV-hFIX16, 1e14 vc/kg of
empty AAV capsid, or saline. We measured expression of human FIX at
18 months by ELISA to confirm stable gene transfer. We determined
the incidence of hepatocellular carcinoma (HCC) at 18 months
post-injection and the incidence of HCC in 9 untreated mice of
equivalent age. We cloned integrated vector copies using LM-PCR and
mapped their genomic locations using 454 pyrosequencing. We
performed microarray analysis on tumor tissue and adjacent normal
tissue to determine if genes near integrated vector became
dysregulated in their expression.
At 18 months we found circulating hFIX levels of 12 ug/mL in mice
receiving 5e12 vg/kg, and 25 ug/mL in mice receiving 1e14 vg/kg,
with no detectable hFIX in mice receiving empty capsid or saline.
We found an HCC incidence rate of 9.1% in untreated mice, 0% in
mice receiving saline or empty capsid, 3.8% in mice receiving 5e12
vg/kg, and 12.5% in mice receiving 1e14 vg/kg (p=0.64 comparing AAV
treated to controls,), although the study was only powered to
detect a 10% difference in HCC incidence. We cloned 251 unique
integrant locations from tumor tissue. We found the expression
changes of genes near integrants did not significantly change more
than genes not near integrants (p=0.46).
Our large-scale prospective study of mice receiving AAV-hFIX16
demonstrated long-term stable gene transfer, but did not
demonstrate a statistically significant difference in HCC
incidence. When analyzing integrated vector in tumor tissue, we
found that genes near these integrants were not any more
dysregulated than genes not near integrants. These results suggest
stable gene transfer of FIX is possible and that integrated AAV
does not dysregulate nearby genes to promote oncogenesis.
September 2010 Issue of IMpact