Resynchronizing the Muscle Ballet

"I was always interested in the application of genetics to human problems," says Eric Hoffman, a molecular geneticist and MDA research grantee who directs the Center for Genetic Medicine Research at Children's National Medical Center in Washington.

In the mid-1980s, as he was finishing his doctorate in biology at Johns Hopkins University, Hoffman says, "I began looking around for a human disease that seemed to be on the cusp of making progress, and Duchenne muscular dystrophy seemed to be number one."

In 1986, Hoffman moved to Children's Hospital and Harvard Medical School in Boston to begin a postdoctoral fellowship with Louis Kunkel, then a new researcher in Duchenne muscular dystrophy (DMD) who had a grant from MDA to study the disease. Later that same year, Kunkel and Hoffman (armed with his own MDA grant) and others identified mutations in the gene for a previously unknown muscle protein as the underlying cause of DMD.

The muscle protein would soon be known as "dystrophin."

Hoffman and Kunkel have remained major figures in DMD research ever since, and both have continued to receive MDA support. Kunkel has remained at Harvard, while Hoffman moved from Harvard to the University of Pittsburgh in 1990 and then to Children's National and George Washington University in Washington in 1999.

Beyond genetic mutations

The dystrophin findings were no doubt among the most important advances in DMD made since the first descriptions of the disease more than a century earlier. But by the late 1990s, Hoffman was looking beyond the mutations themselves.

"Historically, the focus was on the primary gene defect," he says. "People talk about a genetic mutation as 'ground truth,' and in many respects, it is. But the primary gene defect is not the be-all and end-all to everything. It's the initiation of a process, and it's the process — all the things that happen 'downstream' of the genetic defect — that really affects the patient."

Uncoordinated cycles of degeneration and regeneration

These days, what interests Hoffman most among the many downstream effects of dystrophin deficiency in muscle tissue are the chronic and apparently uncoordinated cycles of muscle degeneration and regeneration.

Normally, Hoffman says, an injured muscle fiber goes through degeneration and regeneration as part of an orderly process that takes about two weeks.

"Everything has its time and place,” he explains. “Macrophages [the immune system's first responders] should come in, do their cleanup work in a day or so, then activate muscle stem cells, and then leave, because their job is done.

“Everything is this nicely coordinated ballet stretches over two weeks, with cells coming and going, talking to each other, and then leaving."

Chronic pathology, he says, results from "having a conductor start the orchestra for a ballet and then start it over again every 15 minutes, without telling the group of dancers already on the stage to leave. In Duchenne dystrophy, you can have one region of a muscle that's in day four of the degeneration-regeneration process, a neighboring region that's in day seven, and another neighboring region that's in day one."

Unfortunately, chemical signals released from cells involved in each "ballet" cross the boundaries between fibers, sometimes restarting a dance sequence that should be nearing completion, sometimes prematurely terminating one that's just begun.

Resynchronizing cycles of degeneration and regeneration

Hoffman thinks the action of prednisone — a corticosteroid drug that's widely used to treat DMD — may help with this “uncoordinated ballet,” but in a way that's different from what most people think.

The traditional way of looking at prednisone, he notes, is that it's a potent anti-inflammatory drug. That may be so, Hoffman says, but prednisone may not be directly involved in shutting off inflammation. Instead, it may be doing so indirectly, by resynchronizing the degeneration-regeneration ballet.

Prednisone, he notes, is derived from cortisol, a hormone secreted by the adrenal glands. Cortisol is a master timekeeper, coursing through the circulation at 3 or 4 a.m. and nearly gone by midafternoon every day, its waxing and waning concentrations influencing the timing of many biological events.

Cortisol and its derivatives, such as prednisone, appear to "loudly tap the conductor's podium," Hoffman says, telling the performers, "We're starting again. Everyone back to your original places."

The other effects of cortisol and prednisone are related to their ability to switch genes on and off in cell nuclei, with a variety of consequences. This gene switching, which some experts think of as the primary beneficial effect of prednisone, is to Hoffman's way of thinking the primary culprit behind unwanted side effects such as weight gain, bone thinning and cataracts.

Modifying corticosteroids

In 2008, Hoffman started Validus Biopharma with medicinal biochemist John McCall and muscle inflammation expert Kanneboyina Nagaraju. The goal of this small company is to develop modified corticosteroids that can resynchronize degeneration and regeneration cycles in muscle and other tissues without doing the other things that these drugs do, because they don't switch genes on and off.

(Validus has a grant from MDA Venture Philanthropy, the drug development arm of MDA's translational research program. Hoffman has additional MDA support to study the mechanism by which corticosteroids act in DMD.)

"We've shown that Validus Biopharma drugs can resynchronize tissue remodeling," Hoffman says, "so you don't have the poor cross-talk with the nasty wrong signals. The signals aren't running into each other as much. They're coordinated. If you give them to dystrophin-deficient mice, you get rid of all the inflammation, but you don’t see the side effects of prednisone."

Hoffman says he hopes Validus will be able to test one of its modified corticosteroids in patients with DMD in 2012.