EXON SKIPPING RESCUES CARDIAC,
SKELETAL MUSCLES IN MD MICE

TUCSON, Ariz., Sept. 15, 2008 — The Muscular Dystrophy Association today announced that researchers coordinated by MDA grantee Qi Long Lu at Carolinas Medical Center in Charlotte, N.C., have shown in mice that an experimental treatment for Duchenne muscular dystrophy (DMD) known as "exon skipping" can treat the heart, in addition to other muscles. Exon skipping tells cells to ignore, or "skip over," genetic errors.

The team, which also included MDA grantee Kanneboyina Nagaraju at Children's National Medical Center in Washington, published its findings online today in Proceedings of the National Academy of Sciences.

"We’re pleased to be funding investments in preclinical work, like Qi Lu's approach, that are likely to pay off in more effective therapeutic approaches in the clinic," said Sharon Hesterlee, MDA vice president of translational research.

Using modified versions of previously developed exon-skipping compounds, the investigators found that mice missing the dystrophin protein and with symptoms resembling DMD produced the needed dystrophin in both cardiac and skeletal muscles following treatment. Until now, exon skipping has not been effective in the heart in DMD mice.

Exon skipping is a strategy in which laboratory-developed chemical sequences known as "antisense" are used to block specific sections (exons) of a gene. Antisense sequences are designed to target a specific exon that contains an error (mutation) and allow the cell to splice together the surrounding parts of the gene.

The resulting, nearly correct, genetic instructions can then be used to make a functional protein (in this case, dystrophin). The technique has shown promise in laboratory animals and in a small study conducted in the Netherlands in boys with DMD.

The Lu group used a construction called PPMOE23, targeting exon 23 in dystrophin-deficient mice. They saw no unwanted immune response against PPMOE23, even when it was delivered intravenously.

Because it will be necessary to treat the heart and not just the skeletal muscles in boys with DMD, these results add significant support for the development of exon skipping as a therapy for this disease.

Another research group, coordinated by Ryszard Kole at AVI BioPharma in Corvallis, Ore., published similar results in the September issue of Molecular Therapy.

The Kole group called its compound PPMO M23D-B and also delivered it systemically to dystrophin-deficient mice, where it led to high and sustained dystrophin protein production in skeletal and cardiac muscles without detectable toxicity.

About Duchenne Muscular Dystrophy

The most common form of muscular dystrophy affecting children, DMD strikes one in 3,500 boys. It causes progressive weakness of the skeletal, heart and respiratory muscles beginning in early childhood, and it usually results in death by the early 30s. In the late 1980s, MDA-supported researchers identified the underlying genetic defect in DMD as any of a number of abnormalities in the X-chromosome gene that carries instructions for the muscle protein dystrophin.

About MDA

MDA is a voluntary health agency working to defeat muscular dystrophy and related muscle diseases through programs of worldwide research, comprehensive services, and far-reaching professional and public health education. For more information, visit www.mda.org.