Silencing the FOP gene

@article{Lowery2012SilencingTF,
  title={Silencing the FOP gene},
  author={Jonathan Wayne Lowery and Veronica Lenge de Rosen},
  journal={Gene Therapy},
  year={2012},
  volume={19},
  pages={701-702}
}
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… 
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References

SHOWING 1-10 OF 37 REFERENCES
Role of Altered Signal Transduction in Heterotopic Ossification and Fibrodysplasia Ossificans Progressiva
TLDR
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
TLDR
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?
TLDR
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
TLDR
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.
TLDR
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
TLDR
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
TLDR
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.
TLDR
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.
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