Fibrodysplasia Ossificans Progressive: Potential Therapy

Lara C. Pullen, PhD

September 02, 2015

Working in a mouse model of fibrodysplasia ossificans progressive (FOP), researchers find that an antibody that blocks the ligand activin A effectively stopped abnormal bone formation.

Sarah J. Hatsell, PhD, from Regeneron Pharmaceuticals in Tarrytown, New York, and colleagues published their study online September 2 in Science Translational Medicine.

"[The study] speaks to the enormously valuable fundamental insights into human biology that these rare conditions can provide," said Michael Zasloff, MD, PhD, from Georgetown University Hospital in Washington, DC, in an interview with Medscape Medical News. "It is really a beautifully done paper," he added.

Investigators have known for several years that FOP is caused by a mutation in the ACVR1 receptor of bone morphogenetic protein, ACVR1 R206H . However, until now, investigators thought the mutation itself caused hyperactivity of receptor signaling and bone formation.

Instead, Dr Hastell and colleagues found that the mutant receptor is stimulated by binding to the activin A ligand, which normally represses ACVR1 signaling. The binding reaction between ACVR1 R206H and activin A stimulates receptor signaling and triggers abnormal bone formation. Thus, activin A is both necessary and sufficient to drive heterotopic ossification (HO) in the mouse model of FOP.

Cautiously Optimistic

The investigators engineered a genetically humanized mouse model of FOP (Acvr [R206H]FlEx ) that is both physiologically relevant and versatile. The mouse is a knock-in of the common FOP allele and was achieved with minimal alterations of the native locus.

The team was surprised to discover that ACVR [R206H] demonstrated a gain of function, in that it responded to activin A. In wild-type cells, activin A can act as a competitive inhibitor of signaling from ACVR1 by locking ACVR1 into a nonactive complex with ACVR2.

When the investigators treated the FOP-model mice with a blocking antibody to activin A, they were able to completely inhibit the development of HO.

"We would like to caution, however, that there is a paucity of data implicating activin A as the driver of HO in FOP patients per se; this is largely due to the inability to safely biopsy patients in between, or during, attacks. We cannot therefore formally exclude the possibility that other ligands play a role in the development of HO in FOP patients. Nonetheless, given the high degree of evolutionary conservation in this signaling system as well as in the process of bone formation overall, together with the fidelity of our genetically humanized mouse model in mimicking the human disease, we are cautiously optimistic about exploring activin A blockade in FOP patients," the authors write.

FOP is episodic in nature, and patients may have long periods that are free of HO activity. The researchers suggest that the human antibody to activin A may serve as a treatment, especially during high-risk periods of life.

Most of the authors are employees of Regeneron Pharmaceuticals Inc and hold stock in the company. The remaining coauthor and Dr Zasloff have disclosed no relevant financial relationships.

Sci Transl Med. Published online September 2, 2015. Abstract

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