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Fighting HIV With
HIV: New Gene Therapy Vector
Shows Promise in Penn HIV
Study
 (Philadelphia,
PA) - Researchers at the
University of Pennsylvania
School of Medicine
report the first clinical
test of a new gene therapy
based on a disabled AIDS
virus carrying genetic
material that inhibits HIV
replication. For the first
application of the new
vector five subjects with
chronic HIV infection who
had failed to respond to at
least two antiretroviral
regimens were given a single
infusion of their own immune
cells that had been
genetically modified for HIV
resistance.
The researchers, led by
Carl June, MD, and
Bruce Levine, PhD, of
the Abramson Family Cancer
Research Institute and the
Department of Pathology and
Laboratory Medicine, along
with Rob Roy MacGregor,
MD, Professor of
Medicine, report their
findings in the online
edition of the
Proceedings of the National
Academy of Sciences.
Viral loads of the patients
remained stable or decreased
during the study, and one
subject showed a sustained
decrease in viral load.
T cell counts remained
steady or increased in four
patients during the
nine-month trial.
Additionally, in four
patients, immune function
specific to HIV improved.
Overall, the study results
are significant, say the
researchers, because it is
the first demonstration of
safety in humans for a
lentiviral vector (of which
HIV is an example) for any
disease. Additionally, the
vector, called VRX496,
produced encouraging results
in some patients where other
treatments have failed.
“The goal of this phase I
trial was safety and
feasibility and the results
established that,” says
June. “But the results also
hint at something much
more.”
Each patient received one
infusion of his or her own
gene-modified T cells. The
target dose was 10 billion
cells, which is about 2 to
10 percent of the number of
T cells in an average
person. The T cell count was
unchanged early after the
infusions. “We were able to
detect the gene-modified
cells for months, and in one
or two patients, a year or
more later,” says Levine.
“That’s significant –
showing that these cells
just don’t die inside the
patient. The really
interesting part of the
study came when we saw a
significant decrease in
viral load in two patients,
and in one patient, a very
dramatic decrease.
But, cautions Levine, “just
because this has produced
encouraging results in one
or two patients doesn’t mean
it will work for everyone.
We have much more work to
do.” In the current study,
each patient will be
followed for 15 years.
“The new vector is a
lab-modified HIV that has
been disabled to allow it to
function as a Trojan horse,
carrying a gene that
prevents new infectious HIV
from being produced,” says
Levine. “Essentially, the
vector puts a wrench in the
HIV replication process.”
Instead of chemical- or
protein-based HIV
replication blockers, this
approach is genetic and uses
a disabled AIDS virus to
carry an anti-HIV genetic
payload. The modified AIDS
virus is added to immune
cells that have been removed
from the patients’ blood by
apheresis, purified,
genetically modified, and
expanded by a process June
and Levine developed. The
modified immune cells are
then returned to the
patients’ body by simple
intravenous infusion.
This approach enables
patients’ own T cells, which
are targets for HIV, to
inhibit HIV replication –
via the HIV vector and its
anti-viral cargo. The HIV
vector delivers an antisense
RNA molecule that is the
mirror image of an HIV gene
called envelope to the T
cells. When the modified T
cells are given back to the
patient, the antisense gene
is permanently integrated
into the cellular DNA. When
the virus starts to
replicate inside the host
cell, the antisense gene
prevents translation of the
full-length HIV envelope
gene, thereby shutting down
HIV replication by
preventing it from making
essential building blocks
for progeny virus. VRX496
was designed and produced by
the Gaithersburg, Md.
biotech company VIRxSYS
Corp.
The new vector is based on a
lentivirus, a subgroup of
the well-known retroviruses.
The study and its safety
profile to date have now
opened up the field of
lentiviral vectors, which
have potential advantages
over other viral vectors
currently being studied
because they infect T cells
better than adenoviruses, a
commonly used viral vector.
Lentiviruses also infect
non-dividing or slowly
dividing cells, which
improves delivery to cells
such as neurons or stem
cells, thus enabling the
evaluation of gene therapy
in an even wider array of
diseases than before.
Furthermore, lentiviral
vectors insert into cellular
DNA in such a way that may
be safer than other gene
therapy vectors. This is
because lentiviruses appear
to insert differently from
other retroviruses that have
caused side effects in other
trials involving stem-cell
therapy. In addition, gene
insertion by lentiviral
vectors is attractive for
potential therapeutics since
it enables long-term gene
expression, unlike other
viral vectors where
expression is lost over
time.
Penn researchers are now
recruiting for a second
trial using the VRX496
vector with HIV patients
whose virus is well
controlled by existing
anti-retroviral drugs, a
group of patients who are
generally healthier and have
more treatment options
available. This trial will
use six infusions rather
than one and is designed to
evaluate the safety of
multiple infusions and to
test the effect of infusions
on the patients’ ability to
control HIV after removal of
their anti-retroviral drugs.
The hope is that this
treatment approach may
ultimately allow patients to
stay off antiretroviral
drugs for an extensive
period, which are known to
have significant toxicity,
especially after long-term
use.
The research was supported
by the National Institute of
Allergy and Infectious
Disease; the Abramson Family
Cancer Research Institute;
and VIRxSYS Corp. In
addition to June, Levine,
and MacGregor, co-authors on
the paper are: Jean Boyer
and Frederic Bushman from
Penn; Laurent M. Humeau,
Tessio Rebello, Xiaobin Lu
(now with US Pharmacopeia),
Gwendolyn K. Binder (now
with Penn), Vladimir
Slepushkin, Frank Lemiale,
and Boro Dropulic (now with
Lentigen Corp, Baltmore)
from VIRxSYS; and John R.
Mascola from the National
Institutes of Health.
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