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DMD Gene Therapy

by Margaret Wahl

Real progress is being made in supplying functional dystrophin genes to treat Duchenne muscular dystrophy (DMD), a disease in which mutated dystrophin genes keep this critical protein from being produced in muscle fibers.

An MDA-supported clinical trial has shown the procedure to be safe. Higher doses will now be tested.

Meanwhile, investigators are testing various sizes of miniaturized or non-min-iaturized dystrophin genes, tucked inside adenoviral (AV) or adeno-associated viral (AAV) transporters (“vectors”) or inside donated cells.

At the 11th annual meeting of the American Society of Gene Therapy, sponsored in part by MDA, which took place in Boston May 28-June 1, many sessions focused on the problem of overcoming potentially harmful responses of the immune system to the viral vectors, donated cells or even to the new dystrophin protein made from the transferred genes.

Gene therapy surprisingly
effective in aged DMD mice

A research group coordinated by MDA grantee Jeffrey Chamberlain and including MDA grantee Paul Gregorevic, both at the University of Washington-Seattle, has shown that gene therapy using highly miniaturized dystrophin genes can be effective even in aged, dystrophin-deficient mice with a DMD-like disease.

The study, published in the April issue of Molecular Therapy, bodes well for the potential benefit of gene transfer strategies in older patients with DMD.

The investigators injected shortened versions of the dystrophin gene, which is flawed in DMD, into the tail veins of 20-month-old, dystrophin-deficient mice. (These mice normally live about 24 months.) They encased the so-called microdystrophin genes in modified type 6 adeno-associated viral vectors (AAV6), which are known to penetrate muscle tissue effectively.

Eighteen weeks after injection of the microdystrophin genes, the mice showed body-wide production of the dystrophin protein in their muscles, improved function of their respiratory and back leg muscles, and reduced muscle-fiber degeneration.

Jeffrey Chamberlain’s group found gene therapy effective even in aged DMD mice. Above right: Andrew Kilbarger of Lancaster, Ohio, is in the MDA-supported DMD gene therapy clinical trial.

ment for their hearts.

In the May issue of Molecular Therapy, MDA grantee De Wayne Townsend at the University of Michigan in Ann Arbor and colleagues describe experiments conducted to answer this question that reveal the possible hazard of treating skeletal muscles alone in this disease.

Townsend, with MDA grantee Soichiro Yasuda, also at the University of Michigan, and others, bred mice that produced dystrophin only in their skeletal muscles but not in their hearts. In comparison to fully dystrophin-deficient mice, the mice with dystrophin in their voluntary muscles spent more time running in their exercise wheels, but they also sustained five times the amount of cardiac damage and had significant cardiac muscle dysfunction.

“The finding suggests that, in the context of patients with DMD, caution needs to be exercised when considering potential therapeutic approaches that may have efficacy in skeletal and respiratory muscles but very little activity in the heart,” the researchers note.

Other researchers are addressing this issue and looking closely at gene delivery to the heart.

Treating skeletal muscles
alone bad for hearts
Gene therapy improved
cardiac health of
dystrophin-deficient mice

Ever since gene therapy and
other strategies for treating
DMD have been seriously
contemplated, doctors
have wondered what
might happen to patients
if they became more
active because of better
skeletal muscle function
but didn’t receive treat-

Gene therapy using a microdystrophin gene inside an AAV9 vector markedly improved cardiac function when it was given to newborn mice missing the dystrophin protein, a new study shows.

MDA grantee Dongsheng Duan at the University of Missouri, and colleagues, who published their findings online June 17 in Human Gene Therapy, found this combination led to production of a shortened dystrophin protein throughout the