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HIV, the virus that causes AIDS, may be adapted for use in gene therapy to
treat genetic diseases and immune system disorders including AIDS itself,
according to a Carolina scientist.
New findings released June 24 in the journal Molecular Therapy provide the
first evidence that a genetically stripped-down amalgam of HIV components not
only can safely deliver genes to target cells in the body, but can be fashioned
with a molecular switch system that turns these genes off in response to a
common antibiotic.
This accomplishment was achieved without toxic affects in laboratory rats. It
suggests that doctors may someday be able to control gene expression in people
who are treated with gene therapy vectors based on HIV.
With such control, genes can be switched off when no longer needed, say, for
example, in the production of growth hormone. And if adverse affects develop,
gene expression can be curtailed.
The new study was led by Tal Kafri, assistant professor of microbiology and
immunology in the School of Medicine. Kafri conducted the study while he was a
postdoctoral scientist with Inder M. Verma at the Salk Institute in La Jolla,
Calif. In earlier experiments, Kafri and others had studied the potential
feasibility of gene therapy viral vectors based on lentiviruses, a subfamily of
retroviruses. HIV is a lentivirus.
"One advantage of HIV and other lentiviruses is that they can introduce the
gene of interest into cells that do not divide, and simple retroviruses cannot
do that," Kafri said. "This makes them ideal for delivering genomic material
directly into the body because most of our cells do not divide. This is very
important for transducing (transferring genetic material to) hemopoietic stem
cells (precursor blood cells) because most of them are quiescent and do not
divide."
Kafri, a member of Carolina's Gene Therapy Center, said retroviruses are unique
in that they can integrate their genome into the host's genome. "Unlike
adenovirus -- another virus used as a vector in gene therapy research -- you
don't lose the genomic sequence that is incorporated into the host DNA
following cell division," he said.
Thus, as hemopoietic stem cells develop, they will continue carrying the gene
that was introduced therapeutically via vectors based on HIV.
"Another advantage in using a lentiviral vector is its large capacity," Kafri
said. "It's much larger than a simple retrovirus, which means you can put more
genes and more genomic material in the same vector."
To produce his HIV-based vector, Kafri separated the viral genome into several
components.
"Each of these alone cannot become a virus, but once together in the cell, one
component contributes proteins, another contributes nucleic acid, and the third
contributes non-HIV envelope proteins," Kafri said. The molecular switch system
and the regulated therapeutic genes can be packaged in the form of RNA for
transduction.
In the new study, the vector with its components and payload was injected into
the brains of 12 rats. When expressed -- switched on -- a "reporter gene" for
research purposes showed as green fluorescence in brain cells. After the
antibiotic doxycycline was added to the animals' drinking water, fluorescence
dramatically diminished. Withdrawal of antibiotic from the drinking water was
followed by return of fluorescence.
"These studies show that an inducible lentiviral vector can deliver and
regulate transgene expression in vivo," the authors wrote in the journal
article. "We believe that regulated gene expression is an essential tool for
successful gene therapy approaches."
Kafri said the success of gene therapy would rise and fall with the vector.
In terms of his lentivirus vector, Kafri said the huge advantage is that it's
the most efficient at transducing hemopoietic stem cells.
"This carries implications for treating blood disorders such as Fanconi anemia,
thalassemia and sickle cell anemia; Gaucher's disease, an inherited enzyme
deficiency; and diseases of immune deficiency," he said.
And might that meant targeting HIV? "Sure, if you want to target HIV, a
lentivirus vector would be the vector of choice," he said.
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