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Blood, 15 June 2001, Vol. 97, No. 12, pp. 3733-3737
GENE THERAPY
Factors influencing the development of an anti-factor IX (FIX)
immune response following administration of adeno-associated
virus-FIX
Ying Ge,
Sandra Powell,
Melinda Van
Roey, and
James G. McArthur
From Cell Genesys, Foster City, California.
The present study sought to determine the impact of the route of
administration of an adeno-associated virus (AAV) vector encoding human
factor IX (hFIX) on the induction of an immune response against the
vector and its xenogenic transgene product, hFIX. Increasing doses of
AAV-hFIX were administered by different routes to C57Bl/6 mice, which
typically demonstrate significant immune tolerance to hFIX. The route
of delivery had a profound impact on serum hFIX levels as well as the
induction of an anti-hFIX humoral immune response. At all dose levels
tested, delivery of AAV-hFIX by an intramuscular (IM) route induced an
antibody response against the human FIX protein and no hFIX was
detected in the serum of animals even at doses of
2 × 1011 DNA viral particles (vp) of AAV-hFIX. This was
in stark contrast to the mice that received AAV-hFIX by intraportal
vein (IPV) administration. No anti-hFIX inhibitors were observed in any
of these mice and therapeutic levels of hFIX were detected in the serum
of all mice that received doses of 2 × 1010 vp AAV-hFIX
and higher. When pre-existing neutralizing immunity to AAV was
established in mice, AAV-hFIX administration by either the IM or IPV
routes did not result in detectable serum hFIX. Although hFIX
expression was not observed in mice with pre-existing neutralizing
immunity to AAV, an anti-hFIX response was induced in all of the
animals that received AAV-hFIX by the IM route. This was not observed
in the preimmune mice that received AAV-hFIX by IPV administration.
These results suggest that the threshold of inducing an immune response
against a secreted transgene product, in this case the xenoprotein
hFIX, is lower when the vector is administered by the IM route even in
animals with pre-existing immunity to AAV.
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