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Editorial
. 2016 Oct;4(Suppl 1):S28.
doi: 10.21037/atm.2016.10.62.

Towards a cure for Fibrodysplasia ossificans progressiva

Gonzalo Sanchez-Duffhues  1 , David J J de Gorter  2 , Peter Ten Dijke  1
Affiliations
Editorial

Towards a cure for Fibrodysplasia ossificans progressiva

Gonzalo Sanchez-Duffhues et al. Ann Transl Med. 2016 Oct.
No abstract available

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Conflict of interest statement

The authors have no conflicts of interest to declare.

Figures

Figure 1
Figure 1
Inflammation-induced activin A is able to interact with receptor complexes incorporating the mutant ALK2 in order to induce downstream phosphorylation and activation of intracellular Smads 1/5/8, also called Receptor Smads (or R-Smads). They regulate the expression of genes involved in osteoblast differentiation and HO, as part of transcriptional complexes with other cellular factors. Normalization of the over-active mutant receptor has been intended by downregulating the expression of the receptor (using micro RNAs, exon-skipping or allele specific siRNA-mediated knock-down) or blocking its kinase activity using small molecule kinase inhibitors, which interfere with both the wild type and mutant allele. Hatsell et al. demonstrate the efficacy of type II-Fc constructs (sequestering several BMP and activin ligands) and an anti-activin A specific antibody to prevent ALK2-FOP induced Smad 1/5/8 signaling. These new extracellular strategies (depicted in red) may be complemented with inhibins and activin pro-domains (not tested thus far), or follistatins. Finally, a RAR-γ agonist that inhibits osteoblast differentiation (Palovarotene, Clementia Inc.) is currently being evaluated in Phase II clinical trials (NCT02279095, NCT02521792). Altogether, it remains to be determined whether activin-based therapies are effective in humans, which may benefit of combined treatments with anti-inflammatory drugs.
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References

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