The FOP Story

Our Research Findings

Our research at Regeneron has focused on characterizing the difference in activity between normal and mutant ACVR1, and linking the difference back to the observation that inflammation appears to precede heterotopic ossification (HO) (see The FOP Story – A Brief History of Research Into FOP).

FOP Mouse Model Appears to Recapitulate Human Disease

We have created a mouse model of FOP that has the same ACVR1[R206H] mutation as ~97% of people who have FOP. This mutation can be turned on experimentally to start the process of HO.

Activity of Mutated ACVR1 is Ligand-Dependent

A key initial observation made using the FOP mouse model is that HO can be inhibited by broad-acting BMP ligand blockers, thereby demonstrating that ACVR1[R206H] is dependent on ligands for activity. However, these broad-range inhibitors preferentially block a highly conserved subset of the TGF-β superfamily: the activins. The activins are proteins that are expressed in various tissues and have a range of activities such as hormonal homeostasis, gonadal function and the growth and differentiation of musculoskeletal tissues (Harada et al.; Tsuchida et al.). Activin A is one member of this family.

Activin A Mediates Activity of ACVR1[R206H] in the FOP Mouse Model

Activin A has long been known to be expressed during the initial stages of inflammation by cells of the innate immune system (Aleman-Muench and Soldevila). Based on these observations, we hypothesized that activin A could be the ligand that leads to activity of ACVR1[R206H] and, ultimately, HO.

Our studies in culture dishes found that activin A (as well as related members of this family, activin AB and AC, and activin B) forms a complex with ACVR1 and the corresponding type II receptors, yet the resulting complex does not activate the intracellular Smad signaling pathway; in fact, these activins inhibit signaling through normal ACVR1 (Olsen et al.; Hatsell et al.). By contrast, the FOP mutated receptors, such as ACVR1[R206H], exclusively recognized these activins as activating ligands.

FOP and how Activin A ACVR1 Works ACVR1[R206H] is a gain-of-function variant with unprecedented properties. ACVR1[R206H] retains the ligand-binding properties of wild type ACVR1, but gains the ability to respond to a class of ligands called the activins. Activins normally inhibit BMP signaling from this receptor. However, by a yet-to-be deciphered mechanism, when activins drive the formation of a receptor complex that includes mutant ACVR1, that complex now signals the same way as if it were to have been formed by a BMP. Adapted from Hatsell et al.

Taken together, our results indicate that the [R206H] mutation drives FOP in mice due to gain of response to ligands that ordinarily do not activate this receptor (Hatsell et al.; see also Hino et al.).

Blocking Activin A: A Therapeutic Response

The discovery that activin A causes activation of ACVR1[R206H] (as well as other FOP-causing variants of ACVR1) opened up the possibility that HO lesions and the progression of FOP in people might be prevented by blocking activin A therapeutically.

To learn about Regeneron’s therapeutic program in FOP, please see Our Therapeutic Program.

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I would like additional information about Regeneron’s FOP Program

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