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Intellectual & Developmental Disabilities Research Center
Research Projects (Non-Federal Funding)
Project Title:
Intravascular Injection of Naked Plasmid DNA into the mdx Mouse
Model for DMD
Principal Investigator:
Jon Wolff, MD
Gene therapy promises to be a cure for
the muscular dystrophies such as Duchenne muscular dystrophy. Studies by the
Wolff laboratory and others indicate that the transfer of the normal human
dystrophin gene into dystrophic muscle (in the mouse model) prevents the death
of the myofiber. The critical problem now is how to deliver the normal
dystrophin gene to enough of the muscle cells and have it stably expressed in
order to effect a cure. Previously, Wolff has shown that the intravascular
"injection of naked plasmid DNA (pDNA) into limb arteries of rats and non-human
primates (Rhesus monkeys) leads to very high levels of foreign gene expression
in skeletal muscle throughout the limb and without damaging the muscle. Using
the intra-arterial procedure in mdx mice, Wolff has obtained stable expression
of foreign mouse dystrophin in 1-5% of the myofibers for at least 6 months
following, lone injection. Using the intra-arterial procedure in the GRMD dog
model for Duchenne, he has expressed dog dystrophin in over 10% of myofibers in
several limb muscles. Recently, Wolff discovered that he can achieve these same
levels of foreign gene expression using an intravascular route that has several
advantages. These include less invasiveness and greater ease to do repeated
injections. It is hypothesized that this gene transfer method could be used to
deliver the normal human dystrophin gene to the peripheral limbs of patients
with Duchenne muscular dystrophy and in particular to preserve hand function
which is critical for many self-care and communication (i.e., computer) skills.
The subject of this MDA proposal is to apply the intravenous naked pDNA approach
to the mouse mdx model for Duchenne muscular dystrophy. These mouse experiments
(together with the dog model) will provide important pre-clinical data to
determine whether and how to proceed to human clinical trials. |
