T.O.2 Allele-specific silencing against the ALK2 mutants, R206H and G356D, in fibrodysplasia ossificans progressiva (FOP)

Department of Molecular Pharmacology, National Institute of Neuroscience, NCNP, Kodaira, Tokyo, Japan.
Gene therapy (Impact Factor: 4.2). 12/2011; 19(7):781-5. DOI: 10.1038/gt.2011.193
Source: PubMed

ABSTRACT 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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    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.
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    ABSTRACT: Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder characterized by progressive heterotopic bone formation in skeletal muscle tissue. Patients with FOP show malformed digits, osteochondroma, and other skeletal abnormalities due to abnormal patterning during development. Heterozygous mutations in the Activin A receptor type I (ACVR1) gene, which encodes the bone morphogenetic protein (BMP) type I receptor ALK2, have been identified in not only typical FOP patients but also patients with unusually mild or severe clinical features. The serine/threonine kinase activity of ALK2 may be constitutively activated by mutations in the GS domain or the kinase domain. Based on these findings, selective small chemical inhibitors and allele-specific RNAi approaches for mutant ALK2 have been developed for preventing heterotopic bone formation in FOP. Other novel treatments have also been reported to block heterotopic bone formation in patients with FOP. These findings open the door to the next step in FOP treatment and related research.
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