Diverting an Unwanted Protein

When John Knopf co-founded Acceleron Pharma in the spring of 2003, a muscle protein called myostatin had been on his and other researchers’ radar for several years.

The protein had been identified as a “negative regulator” (limiter) of muscle growth and regeneration back in 1997. And, since that time, myostatin-deficient mice and cattle had been shown to have large, strong muscles without any apparent ill effects.

Additionally, two key research papers had been published in 2002, both of which had direct relevance to muscular dystrophy research. They reported experiments conducted in mice lacking a protein called dystrophin and showing a disease resembling human Duchenne muscular dystrophy (DMD).

One set of experiments involved knocking out myostatin genes in dystrophin-deficient (mdx) mice; the other involved mdx mice that were given antibodies (immune system proteins) that blocked myostatin protein activity.

The mdx mice bred not to produce myostatin were stronger and more muscular than their mdx counterparts with normal myostatin levels. And, the mdx mice treated with anti-myostatin antibodies for three months showed more muscle mass and muscle strength, as well as a significant decrease in muscle degeneration, compared with their untreated counterparts.

The combined effects of these findings paved the way for further research and development of myostatin-inhibiting therapies as a potential treatment of DMD and perhaps other muscular dystrophies — and that’s what Knopf and his colleagues at Acceleron wanted to do.

Early research used myostatin antibody

By 2003, Knopf, who has a doctorate in molecular and cellular biology from the State University of New York at Buffalo, had been working in the biotechnology industry for several years. His most recent position had been in the research division of Wyeth, a pharmaceutical company that’s now part of Pfizer.

Wyeth also became interested in blocking myostatin, especially after 2004. In that year, news about a healthy, large-muscled child with a genetic myostatin deficiency reached the world via a paper in the New England Journal of Medicine, igniting the field. The 4-year-old boy, identified in Germany, had almost no myostatin, had large, strong muscles, and had no apparent health problems.

Wyeth developed an antibody to myostatin and began testing it in 2005 in adults with a variety of muscular dystrophies. It would prove to be safe but not beneficial.

“We don’t know much about the Wyeth studies,” says Knopf, who had left Wyeth by the time the company got seriously interested in the subject, “but that’s a big question we get: ‘Didn’t folks already try to inhibit myostatin, and didn’t that fail?’”

Knopf answers that question by emphasizing that the apparent lack of benefit from the anti-myostatin antibody therapy does not mean that inhibiting myostatin and other proteins using a different approach would not be effective.

In fact, he says, data from mouse studies suggest that the “decoy receptor” strategy Acceleron has chosen is much more promising than the antibody strategy.

Mechanism of ACE-031

Normally, myostatin and other negative regulators of muscle dock on receptors called ActRIIB on the muscle-fiber membrane surface. They send signals through these receptors that limit muscle growth and regeneration. ACE-031 is designed to be a circulating "decoy" ActRIIB receptor, capable of trapping myostatin and other negative muscle regulators and diverting them from the surface receptors through which they would normally send their growth-limiting signals.

‘Decoy receptor’ binds myostatin

“Myostatin,” Knopf explains, “binds to a receptor (docking site) that’s present on the surface of cells. When it binds to that receptor, it tells the body to make less muscle.” It’s that interaction of myostatin with a receptor called ActRIIB that Knopf and his colleagues at Acceleron want to interrupt.

Knopf’s team created a decoy ActRIIB receptor, one that dissolves in blood and can bind circulating myostatin. Myostatin stuck to this decoy is unable to bind to its naturally occurring receptors, and it’s diverted from its normal role, which is signaling muscle to stop growing or regenerating.

Knopf also points out that there are other proteins related to myostatin that normally stick to ActRIIB receptors and that these too limit muscle growth, development and regeneration in different ways and at different time points.

“The idea is to inhibit several of these proteins at once with one decoy,” Knopf says, “with the potential not only to increase the muscle mass, but also to affect the overall quality of the muscles.”

ACE-031 now being tested in boys with DMD

Acceleron recently began testing their soluble form of ActRIIB, called ACE-031, in boys with DMD in Canada. In September 2010, Acceleron entered a collaboration with the specialty biopharmaceutical company Shire in which the companies will jointly collaborate on a worldwide development program to advance ACE-031 into a global phase 2/3 clinical program designed to demonstrate long-term disease modification in DMD patients.

In January 2011, MDA awarded a $1.5 million grant to Acceleron to support and expand the ongoing clinical studies of ACE-031 in boys with DMD.

“We’re optimistic that indeed we’ll show some efficacy for muscular dystrophy,” says Knopf. “We’re hoping for stronger muscles and muscles that are less susceptible to damage — which is the opposite of what you get in muscular dystrophy, where you see weakening muscles that are more susceptible to damage. We hope to reverse that course.”

For information about the ACE-031 trials in Canada, contact Rhiannon Taranik at (519) 685-8441 or Rhiannon.Taranik@lhsc.on.ca, or send email to clinicaltrials@acceleronpharma.com.