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Antisense-oligonucleotide mediated exon skipping in activin-receptor-like kinase 2: inhibiting the receptor that is overactive in fibrodysplasia ossificans progressiva.
PLoS One. 2013; 8(7):e69096.Plos

Abstract

Fibrodysplasia ossificans progressiva (FOP) is a rare heritable disease characterized by progressive heterotopic ossification of connective tissues, for which there is presently no definite treatment. A recurrent activating mutation (c.617G→A; R206H) of activin receptor-like kinase 2 (ACVR1/ALK2), a BMP type I receptor, has been shown as the main cause of FOP. This mutation constitutively activates the BMP signaling pathway and initiates the formation of heterotopic bone. In this study, we have designed antisense oligonucleotides (AONs) to knockdown mouse ALK2 expression by means of exon skipping. The ALK2 AON could induce exon skipping in cells, which was accompanied by decreased ALK2 mRNA levels and impaired BMP signaling. In addition, the ALK2 AON potentiated muscle differentiation and repressed BMP6-induced osteoblast differentiation. Our results therefore provide a potential therapeutic approach for the treatment of FOP disease by reducing the excessive ALK2 activity in FOP patients.

Authors+Show Affiliations

Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23861958

Citation

Shi, Songting, et al. "Antisense-oligonucleotide Mediated Exon Skipping in Activin-receptor-like Kinase 2: Inhibiting the Receptor That Is Overactive in Fibrodysplasia Ossificans Progressiva." PloS One, vol. 8, no. 7, 2013, pp. e69096.
Shi S, Cai J, de Gorter DJ, et al. Antisense-oligonucleotide mediated exon skipping in activin-receptor-like kinase 2: inhibiting the receptor that is overactive in fibrodysplasia ossificans progressiva. PLoS One. 2013;8(7):e69096.
Shi, S., Cai, J., de Gorter, D. J., Sanchez-Duffhues, G., Kemaladewi, D. U., Hoogaars, W. M., Aartsma-Rus, A., 't Hoen, P. A., & ten Dijke, P. (2013). Antisense-oligonucleotide mediated exon skipping in activin-receptor-like kinase 2: inhibiting the receptor that is overactive in fibrodysplasia ossificans progressiva. PloS One, 8(7), e69096. https://doi.org/10.1371/journal.pone.0069096
Shi S, et al. Antisense-oligonucleotide Mediated Exon Skipping in Activin-receptor-like Kinase 2: Inhibiting the Receptor That Is Overactive in Fibrodysplasia Ossificans Progressiva. PLoS One. 2013;8(7):e69096. PubMed PMID: 23861958.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Antisense-oligonucleotide mediated exon skipping in activin-receptor-like kinase 2: inhibiting the receptor that is overactive in fibrodysplasia ossificans progressiva. AU - Shi,Songting, AU - Cai,Jie, AU - de Gorter,David J J, AU - Sanchez-Duffhues,Gonzalo, AU - Kemaladewi,Dwi U, AU - Hoogaars,Willem M H, AU - Aartsma-Rus,Annemieke, AU - 't Hoen,Peter A C, AU - ten Dijke,Peter, Y1 - 2013/07/04/ PY - 2013/02/16/received PY - 2013/06/04/accepted PY - 2013/7/18/entrez PY - 2013/7/19/pubmed PY - 2014/2/4/medline SP - e69096 EP - e69096 JF - PloS one JO - PLoS One VL - 8 IS - 7 N2 - Fibrodysplasia ossificans progressiva (FOP) is a rare heritable disease characterized by progressive heterotopic ossification of connective tissues, for which there is presently no definite treatment. A recurrent activating mutation (c.617G→A; R206H) of activin receptor-like kinase 2 (ACVR1/ALK2), a BMP type I receptor, has been shown as the main cause of FOP. This mutation constitutively activates the BMP signaling pathway and initiates the formation of heterotopic bone. In this study, we have designed antisense oligonucleotides (AONs) to knockdown mouse ALK2 expression by means of exon skipping. The ALK2 AON could induce exon skipping in cells, which was accompanied by decreased ALK2 mRNA levels and impaired BMP signaling. In addition, the ALK2 AON potentiated muscle differentiation and repressed BMP6-induced osteoblast differentiation. Our results therefore provide a potential therapeutic approach for the treatment of FOP disease by reducing the excessive ALK2 activity in FOP patients. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/23861958/Antisense_oligonucleotide_mediated_exon_skipping_in_activin_receptor_like_kinase_2:_inhibiting_the_receptor_that_is_overactive_in_fibrodysplasia_ossificans_progressiva_ L2 - https://dx.plos.org/10.1371/journal.pone.0069096 DB - PRIME DP - Unbound Medicine ER -