Disease-causing allele specific silencing against the ALK2 mutants, R206H and G356D, in Fibrodysplasia Ossificans Progressiva

Department of Molecular Pharmacology, National Institute of Neuroscience, NCNP, Kodaira, Tokyo, Japan.
Gene therapy (Impact Factor: 3.1). 12/2011; 19(7):781-5. DOI: 10.1038/gt.2011.193
Source: PubMed


Fibrodysplasia ossificans progressiva (FOP) is an autosomal dominant congenital disorder characterized by progressive heterotopic bone formation. Currently, no definitive treatment exists for FOP. The activin receptor type IA / activin-like kinase 2 (ACVR1/ALK2) gene has been identified as the responsible gene for FOP, and disease-associated ALK2 mutations have been found. Chemical inhibitors to the pathogenic ALK2 receptors are considered possible medical agents for FOP, but their adverse effects on normal ALK2 and other receptors cannot be excluded. Here we describe another treatment strategy for FOP using allele-specific RNA interference (ASP-RNAi), and show modified small interfering RNAs (siRNAs) conferring allele-specific silencing against disease-causing ALK2 mutants found in FOP, without affecting normal ALK2 allele. Thus, the siRNAs presented here may become 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.

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Available from: Hirohiko Hohjoh, Jul 07, 2015
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    • "The ideal BMP inhibitor for FOP patients would be an agent that normalizes the (excessive) ALK2 activity without affecting the functions of other kinases. Using the allele specific siRNA technique, two separate research groups have successfully obtained siRNAs that target the disease-causing ALK2, without affecting normal ALK2 expression [15], [16]. The siRNAs were used in cells from FOP patients to restore BMP activity and osteogenic differentiation [15], [16]. "
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    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.
    Full-text · Article · Jul 2013 · PLoS ONE
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    • "ALK2 mutants found in FOP, without affecting normal ALK2 allele (Takahashi et al., 2012; Kaplan et al., 2012). "
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    ABSTRACT: Fibrodysplasia ossificans progressiva (FOP), characterized by congenital malformation of bones, is an autosomal dominant disorder. This is a rare genetic disorder and its worldwide prevalence is approximately 1/2,000,000. There is no ethnic, racial, gender, or geographic predilection to FOP. It is regarded as one of the intractable disorders, which is not only an extremely disabling disease but also a condition of considerably shortened lifespan. Although the genetic defects of FOP are not completely known, several clinical and animal model studies have implicated that mutations in bone morphogenetic proteins, their receptors, and activin receptor type IA (ACVR1) genes are associated with FOP primarily. The noggin (NOG) gene has also been reported in some studies. In most of the cases of FOP, the mutation was found as 'de novo' however there is paternal age effect on mutations. Unfortunately, at present there is no efficient treatment for FOP. The recent discoveries of genetic basis of FOP provide a clue to the underlying pathophysiology and potential therapy. This review article focuses on the genetic mutations in FOP, their usage as diagnostic markers, and possible target specific drug development to treat FOP patients.
    Full-text · Article · Dec 2012 · Genes & Genetic Systems
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    ABSTRACT: Transforming growth factor-β family members, which include TGF-βs, activins and bone morphogenetic proteins (BMPs), play important roles in development and maintaining tissue homeostasis. The extracellular TGF-β family members signal across the plasmamembrane by activating type I and type II serine/threonine kinase receptors. Pertubation in TGF-β family receptor signaling has been implicated in certain diseases, including musculo-skeletal disorders. Fibrodysplasia ossificans progressiva (FOP) is a rare disorder characterized by progressive formation of ectopic bone and congenital malformations of the great toes. At present no curative therapy is available, therefore prevention of heterotopic ossification is the hallmark of FOP management. FOP has been linked to an autosomal dominant mutation on chromosome 2, to the gene encoding activin receptor-like kinase 2 (ALK2), a BMP type I receptor. This mutation is found in almost all classically affected FOP patients and causes the FOP phenotype. This discovery has paved the way for further investigations into the molecular basis underlying FOP and has recently pointed towards potential strategies to treat this devastating disease.
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