UC Berkeley dean’s research inspires emerging treatment for rare bone disease

Regeneron Pharmaceuticals, Inc. announced on September 17 that it had completed a phase 3 trial for a drug to treat fibrodysplasia ossificans progressiva (FOP). FOP is a severe, ultra-rare genetic disorder that forms bone in connective tissues, which may significantly restrict mobility and result in an early death. Regeneron’s trial medicine reduced new bone lesions in FOP patients by over 90 percent. 

After announcing the positive news, Aris Economides, vice president of research at Regeneron, shared his excitement with UC Berkeley’s dean of biological sciences, Richard Harland. It was Harland’s mid-1990s discovery of a gene and its associated protein that prompted Regeneron down a winding path that eventually led to its potential FOP treatment — a demonstration of basic research’s value to society.

In 1992, Harland and his postdoctoral fellow at the time, William Smith, were investigating how frog embryos form their backs and bellies. They found the protein responsible for developing the brain and spinal cord and named it noggin, as high doses of this protein resulted in larger heads. Harland worked with UC Berkeley’s Office of Technology Licensing to offer businesses the chance to turn his research into clinical treatments. Regeneron expressed interest. 

Four years later, the Harland Lab discovered that noggin stops bone development by inhibiting a specific bone morphogenetic protein (BMP). This realization meant that noggin also has a blocking effect in embryonic tissues and that cells turn into neural tissues when not instructed otherwise by BMPs — fundamental concepts that changed how developmental biologists understood the body. Additionally, the finding suggested that noggin could be used to inform research in disorders like FOP.

“We would never have looked at FOP if it wasn't for the noggin connection back then,” said Economides. “It opened the door to a very, very puzzling disease.”

Unfortunately, noggin has a narrow therapeutic window and some negative side effects. The medical community kept searching.

A University of Pennsylvania-led team found that a genetic mutation causes FOP. Economides and his Regeneron colleagues expanded on that initial finding by demonstrating that the mutation misinterprets the Activin A protein as a signal to produce bones. Instead of blocking BMPs, the pharmaceutical company realized it needed to block Activin A.

“Much credit to them for figuring it out,” said Harland. “It took a long time, a lot of work, and other discoveries.”

Resources are often difficult to secure for rare diseases like FOP, which affects approximately one person in 2,000,000. In Regeneron’s case, the company’s leaders told Economides that if he thought he could develop a drug that stopped the disease from progressing, he had an obligation to work on it.

“The biological lessons that I've learned by exploring this genetic disorder, as well as other rare conditions, are absolutely unfathomable,” said Economides. “You have to revise a lot of what you think.”

“You can't predict where an interesting question will take you,” continued Economides. “People love straight lines, but in science, there are hardly ever any straight lines. Usually, it's a twisted path, and the challenge is to see the opportunities when they arise, rather than stick to preconceived notions derived from hypothesis.”

Science doesn’t occur in a vacuum. Each breakthrough inspires future studies. Harland’s initial work built on decades of fundamental research into developmental biology.

Harland is holding out hope for a more general approach that can block excessive bone formation and resolve related conditions like bone spurs. His research may not have directly produced a cure, but it did prompt Regeneron to pursue a path that eventually ended up with one. He is very happy with the results. 

“Overall, it’s a beautiful piece of research over at Regeneron,” said Harland. “Of course, we didn’t participate in that part of the story, but we showed that by poking around at how embryos get their pattern, we can stimulate interest in another field, and eventually a company like Regeneron will pick it up and take it all the way to the finish line.”

As dean, Harland is now working with other faculty members to streamline the lab-to-clinic pipeline, especially for rare, neglected, and emerging diseases. To learn more about this effort, read our interview with Professor Andrew Dillin.