What is Fibrodysplasia Ossificans Progressiva?
 

Fibrodysplasia Ossificans Progressiva (FOP), often referred to as "Stone Man Syndrome," is an extremely rare genetic disorder. It is characterized by congenital bilateral great toe malformations and progressive, widespread, irreversible heterotopic ossification (HO) of soft tissues throughout the body, ultimately leading to severe disability. The incidence is approximately 1 in 1 million.
 

Pathogenesis
 

The pathogenesis of FOP is primarily caused by mutations in the ACVR1 gene, located in the 2q23-24 region. ACVR1 is a Bone Morphogenetic Protein (BMP) type I transmembrane serine/threonine kinase receptor. BMP type I receptors (ACVR1, BMPR1A, BMPR1B) form heterotetramers with BMP type II receptors (such as BMPR2, ACVR2A, and ACVR2B). Upon BMP binding, BMP type II receptors phosphorylate BMP type I receptors, activating downstream signaling pathways. The ACVR1R206H mutation causes the protein to function aberrantly as an activin receptor, leading to constitutive activation of the SMAD1/5/9 signaling pathway and reduced binding affinity for the negative regulator FKBP12, thereby driving heterotopic ossification (HO).
 

Furthermore, Activin A (ACTA), a secreted factor implicated in HO development in FOP, can bind to ACVR1B to activate SMAD2/3 or bind ACVR1 and activin/BMP type II receptors via its finger 2 tip loop, forming a Non-Signaling Complex (NSC). FOP-associated ACVR1 missense mutations can convert the NSC into a signaling complex. The NSC negatively regulates signaling for HO.
 

In addition to ACVR1 and ACTA, TGF-β/BMP family ligands can also signal via non-SMAD cascades, such as through TGF-β-activated kinase 1 (TAK1). In FOP patients, macrophages secrete increased amounts of TGF-β and exhibit prolonged NF-κB and p38 MAPK activation without changes in phosphorylated SMAD1/5 (p-SMAD1/5), indicating dysregulated TAK1 activation, which further promotes HO development.

(Image: PubMed)

 

Gene Therapy
 

1. Gene Silencing Technology: Utilizes RNA interference (RNAi) technology, such as short hairpin RNA (shRNA) or small interfering RNA (siRNA), to silence the mutant ACVR1 gene, reducing the production of the abnormal protein.

2. Gene Editing Technology: Employs gene editing systems like CRISPR/Cas9 to directly repair the ACVR1 gene mutation, or uses base editors or prime editors to correct the mutation.

3. Gene Replacement: Uses viral vectors to deliver a normal copy of the ACVR1 gene into patient cells to replace or compensate for the function of the mutant gene.

 

Mouse Models
 

ACVR1R206H FlEx/+ Conditional Inducible Mice: Used for pathogenesis studies, allowing temporal and cell-type-specific control of mutation activation. Requires trauma for HO triggering, making it the model closest to the human disease.

ACVR1 R206H Knock-in Mice: The mutation is expressed constitutively throughout the body and development, leading to severe developmental abnormalities and low survival rates. Primarily used to study the impact of the mutation on skeletal patterning during embryogenesis.

ACVR1Q207D Mice: Carry the ACVR1 Q207D mutation, which leads to strong, constitutive activation of the BMP signaling pathway, often resulting in spontaneous and extensive HO. Suitable for studying the direct consequences of extreme pathway activation.

BMP4 Overexpression Mice: Overexpress BMP4 (Bone Morphogenetic Protein 4) to mimic abnormal BMP pathway activation seen in FOP.

 

MingCeler Biotech Facilitates Gene Therapy
 

Gene therapy offers hope for rare diseases, but its development and validation are inseparable from animal model support. Leveraging its self-developed TurboMice™ technology, MingCeler Biotech has developed multiple rare disease mouse models. The TurboMice™ technology overcomes the challenges of long modeling cycles and low success rates for complex models. It enables editing at virtually any target gene locus and can generate complete homozygous gene-edited mouse models directly from embryonic stem cells in as little as 2 months.

MingCeler Biotech can customize various FOP mouse models according to client needs, such as ACVR1R206H FlEx/+ conditional inducible mice, ACVR1 R206H knock-in mice, ACVR1Q207D mice, and BMP4 overexpression mice. We welcome inquiries!

 

References:

[1] She D, Zhang K. Fibrodysplasia ossificans progressiva in China. Bone. 2018 Apr;109:101-103. doi: 10.1016/j.bone.2017.11.016. Epub 2017 Nov 22. PMID: 29175272.

[2] Zhou Y, Shi C, Sun H. Advancements in mechanisms and drug treatments for fibrodysplasia ossificans progressiva. J Zhejiang Univ Sci B. 2025 Apr 23;26(4):317-332. doi: 10.1631/jzus.B2300779. PMID: 40274382; PMCID: PMC12021541.

[3] Eekhoff EMW, de Ruiter RD, Smilde BJ, Schoenmaker T, de Vries TJ, Netelenbos C, Hsiao EC, Scott C, Haga N, Grunwald Z, De Cunto CL, di Rocco M, Delai PLR, Diecidue RJ, Madhuri V, Cho TJ, Morhart R, Friedman CS, Zasloff M, Pals G, Shim JH, Gao G, Kaplan F, Pignolo RJ, Micha D. Gene Therapy for Fibrodysplasia Ossificans Progressiva: Feasibility and Obstacles. Hum Gene Ther. 2022 Aug;33(15-16):782-788. doi: 10.1089/hum.2022.023. PMID: 35502479; PMCID: PMC9419966.

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