Silencing the FOP gene

  title={Silencing the FOP gene},
  author={Jonathan Wayne Lowery and Veronica Lenge de Rosen},
  journal={Gene Therapy},
Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disease in which bone is formed in soft tissues through heterotopic ossification (HO). HO is often a problem for patients who have received a traumatic insult, either to musculoskeletal tissues (traumatic HO) or to the skin or spinal cord (neurologic HO). Although trauma-induced HO can be painful, it is often transitory and easily treated with conventional therapies such as bisphosphonates, radiation and surgical removal… 
Druggable targets, clinical trial design and proposed pharmacological management in fibrodysplasia ossificans progressiva
A schema for pharmacological management of FOP in anticipation of approved medications and the availability of repurposed drugs is proposed and new approaches to clinical trial design, including delayed start and n = 1 designs, are considered.
Hard targets for a second skeleton: therapeutic horizons for fibrodysplasia ossificans progressiva (FOP)
This work aims to provide a novel, scalable, and scalable approach to treatments for FOP and related disorders that has real-time applicability in the clinical practice.
Bone Morphogenetic Protein-Based Therapeutic Approaches.
A wide perspective on diseases and/or conditions associated with dysregulated BMP signal transduction is provided, the current strategies available to modulate BMP pathways are outlined, emerging second-generation technologies are highlighted, and prospective avenues for future investigation are postulated.
Agent prophylactique et agent thérapeutique pour la fibrodysplasie ossifiante progressive
L'invention concerne un agent prophylactique ou therapeutique pour la fibrodysplasie ossifiante progressive, ledit agent comprenant, en tant que principe actif, un inhibiteur de liaison inhibant une
The unique activity of bone morphogenetic proteins in bone: a critical role of the Smad signaling pathway
The data in the literature show that the BMP type I receptor – Smad signaling axis is the critical pathway for the unique activity of BMPs and is a potential therapeutic target for pathological conditions caused by inappropriate BMP activity.
A Survey of Strategies to Modulate the Bone Morphogenetic Protein Signaling Pathway: Current and Future Perspectives
A wide-perspective on strategies that increase or decrease BMP signaling is provided, with a particular emphasis on the relationship between the BMP and Activin/TGF-β pathways.
TGF-β/BMP signaling and other molecular events: regulation of osteoblastogenesis and bone formation
Accumulating evidence indicates that Runx2 is the key integrator, whereas Hh is a possible modulator, miRNAs are regulators, and β-catenin is a mediator/regulator within the extensive intracellular network.
Medium-Intensity Treadmill Exercise Exerts Beneficial Effects on Bone Modeling Through Bone Marrow Mesenchymal Stromal Cells
The medium-intensity treadmill exercise enhanced bone formation and increased osteocalcin (OCN) and osteopontin (OPN) mRNA expression as well as activation of the BMP-Smad signaling pathway in vivo.


Role of Altered Signal Transduction in Heterotopic Ossification and Fibrodysplasia Ossificans Progressiva
The discovery that mildly activating mutations in ACVR1/ALK2, a bone morphogenetic protein (BMP) type I receptor, is the cause of FOP has provided opportunities to identify previously unknown functions for this receptor and for BMP signaling and to develop new diagnostic and therapeutic strategies for FOP, as well as tissue engineering applications.
BMP type I receptor inhibition reduces heterotopic ossification
The role of dysregulated ALK2 kinase activity in the pathogenesis of FOP is supported and small molecule inhibition of BMP type I receptor activity may be useful in treating FOP and heterotopic ossification syndromes associated with excessive BMP signaling.
Stromal cells of fibrodysplasia ossificans progressiva lesions express smooth muscle lineage markers and the osteogenic transcription factor Runx2/Cbfa‐1: clues to a vascular origin of heterotopic ossification?
It is hypothesized that the stromal cells of early FOP lesions may be locally recruited vascular cells or cells of the bone marrow stroma and that these cells maintain the potential (given the correct environmental stimuli) to differentiate along an endochondral ossification pathway.
Disease-causing allele-specific silencing against the ALK2 mutants, R206H and G356D, in fibrodysplasia ossificans progressiva
Modified small interfering RNAs (siRNAs) conferring allele-specific silencing against disease-causing ALK2 mutants found in FOP are shown to be novel therapeutic agents for FOP, and their induced ASP-RNAi may pave the way for the achievement of radical treatment of FOP and/or for the relief of its severe symptoms.
Identification of progenitor cells that contribute to heterotopic skeletogenesis.
The data strongly suggest that dysregulation of the BMP signaling pathway and an inflammatory microenvironment are both required for the formation of fibrodysplasia ossificans progressiva-like lesions.
Restoration of normal BMP signaling levels and osteogenic differentiation in FOP mesenchymal progenitor cells by mutant allele-specific targeting
The results provide proof-of-principle that ASP-RNAi has potential therapeutic efficacy for the treatment of FOP and decreased the elevated BMP signaling that is characteristic of patient cells to levels similar to control cells and restored enhanced osteogenic differentiation to control levels.
Circulating Osteogenic Precursor Cells in Heterotopic Bone Formation
It is shown that circulating osteogenic precursor (COP) cells, a bone marrow‐derived type I collagen+/CD45+ subpopulation of mononuclear adherent cells, are present in early preosseous fibroproliferative lesions in patients with fibrodysplasia ossificans progressiva and nucleate heterotopic ossification (HO) in a murine in vivo implantation assay.
Development of allele-specific therapeutic siRNA for keratin 5 mutations in epidermolysis bullosa simplex.
Using a systemic screening system based on a luciferase reporter gene assay, mutant-specific siRNAs are developed for two independent EBS-causing missense mutations in the K5 gene, showing promise for the treatment of EBS and paves the way for future clinical trials.