| January 22,
for Muscular Dystrophy, When Controlled By a Muscle-Specific
Promoter, Prevents Immune Response
In a study of Muscular
Dystrophy, scientists at the University of Pennsylvania
School of Medicine have found that a common delivery
system used in treating the disease through gene therapy
may trigger an immune response in mice unless it is
used in combination with a muscle-specific promoter
that localizes the expression of genetic material.
The study findings are published in the new issue of
the journal Human Gene Therapy. "Even when you
use low-levels of a promoter that is not restricted
to the afflicted area, you run the risk that you will
immunize the patient against the very protein you are
trying to get made," said H. Lee Sweeney, PhD, chairman
of the Department of Physiology at Penn and lead author
of the study. "This is relevant because some of the
clinical trials that have been started are not using
restricted promoters. The journal wanted to get this
message out there."
In their published findings, the Penn researchers state
that it is "crucial" to establish which method should
be used before expanding clinical trials.
The scientists used two groups of mice that had been
engineered to lack a protein called gamma sarcloc-glycan
(gsg) in their muscles, which is the same protein that
is missing in muscluar dystrophy (MD).
The researchers administered the protein to both groups
of mice by enclosing the gsg in the recombinant adeno-associated
virus (rAAV) - a commonly used vector that has been
described in previous scientific research as non-immunogenic.
In one group of mice, the rAAV included a cytomegalovirus
(CMV) promoter -- which will express the DNA material
it carries in any tissue. The results Sweeney found:
"Although we didn't see the immune response in the CMV
promoter in a large percentage of the mice - we did
In the second group of mice, when the rAAV that contained
the gsg material was delivered under the control of
the muscle creatine kinase promoter - which is muscle-specific
-- there was no immune response.
"What we think happens is that if the virus gets into
tissues that are very good at presenting foreign proteins
to the immune system, then an immune response is generated
to any proteins the virus may express," Sweeney said.
"Skeletal muscle (which is affected by MD) is very bad
at presenting - we've never seen an immune response,
as long as the expressed protein is restricted to the
"The issue is: If you put DNA material into a virus
that will fix the disease -will it also trigger an immune
response?" Sweeney said. "The answer appears to be -
possibly. But as long as you keep the protein in the
skeletal muscle and nowhere else, you don't get an immune
response." The study was funded by the National Institutes
of Health, the Muscular Dystrophy Association and the
Association Francaise contre les Myopathies.
Sweeney's collaborators in the research were: Laurence
Cordier, PhD, of Penn's Department of Physiology; Andrew
A. Hack, PhD, and Elizabeth M. McNally, PhD, both of
the University of Chicago, and Guang-Ping Gao, PhD;
Narendra Chirmule, PhD, and James M. Wilson, MD, PhD,
of Penn's Institute for Human Gene Therapy.