Steroid-Coated
DNA Represents New Approach to Gene Delivery
February 11, 2004
PHILADELPHIA -- Coating DNA with a topical steroid might
make for more effective therapeutic gene delivery, according
to bioengineers at the University of Pennsylvania. The researchers
have shown that a common anti-inflammatory steroid, wrapped
around a strand of DNA, can prevent the immune responses commonly
associated with gene-transfer techniques.
Studies of the technique, performed in animal models, are
presented in the Feb. 15 issue of the journal Gene Therapy,
available online now.
"The steroid coating not only allows the gene to be
taken up into a cell more easily, but the steroid itself also
prevents the sort of inflammatory immune response seen in
gene transfer therapy," said Scott Diamond, senior author
and professor of bioengineering at Penn and associate director
of Penn Institute for Medicine and Engineering. "The
concept paves the way to coupling therapeutic gene delivery
with a pharmacological agent, an approach that mitigates some
of the drawbacks to the gene-delivery techniques in use now."
Currently there are two basic approaches to delivering therapeutic
genes: nonviral and viral. Injecting a subject with pure DNA
is possible, but a DNA molecule, by itself, has inherent trouble
in entering cells. Viral carriers can serve as delivery vehicles
for DNA, literally infecting cells with new genes. Both methods,
however, are associated with the creation of inflammatory
immune responses that reduces the action of the therapeutic
gene.
DNA is a large and negatively charged molecule, which is
the source of the stumbling point in getting cells to take
up DNA. To counter the negative charge of DNA, Diamond and
his colleagues took a common steroid, dexamethasone, and made
it sticky by adding a nitrogen-rich, positively charged tail.
This tail provides the glue that attaches the steroid to the
naked DNA.
"The steroid is a fatty lipid so, in essence, we have
greased up DNA for cellular uptake," Diamond said, "Plus
the cells get a big dose of steroid."
According to Diamond, the chemistry involved in manufacturing
this new steroid vehicle is a fairly straightforward, one-step
process that is simple compared to creating viral gene therapy
vectors.
"But this is more than just gene therapy on steroids,"
Diamond said. "The dexmethasone not only eased inflammation
in an animal model, but, as our study showed, actually allowed
the cells to use the foreign DNA more effectively."
In addition, corticosteroids can suppress the major inflammatory
cytokines created by the immune response after gene delivery.
According to studies in cell culture and animal models, the
steroid-coated DNA showed lower initial inflammation and greater
expression of the gene over time. The results have encouraged
the researchers to continue studies and to envision broader
application of the technique toward diseases that might also
benefit from gene-transfer therapy.
"In humans, especially in inflammatory diseases, a steroid
coating would greatly enhance the chances of successful gene
transfer," Diamond said. "As an alternative, I could
foresee the use of this coating technique to tailor therapies
by choosing drugs that would amplify the benefit of a particular
therapeutic gene."
Funding for this research was supported by grants from the
National Institutes of Health and the Cystic Fibrosis Foundation.
Contact: Greg Lester
215-573-6604
glester@pobox.upenn.edu
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