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

Abstract

Abstract Fibrodysplasia ossificans progressiva (FOP) is an autosomal dominant congenital disorder characterized by postnatal progressive heterotopic ossification in soft tissues, especially skeletal muscle. In FOP, acute heterotopic ossification is induced by muscle injury, such as accidental trauma or surgical operations. 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 both familial and sporadic cases of FOP, and disease-associated ALK2 mutations have been found. ALK2 protein, which is one of the signaling receptors for bone morphogenetic proteins (BMPs) and which induce heterotopic bone formation in skeletal muscle in vivo and initiate the differentiation pathway through which myoblasts convert to osteoblastic cells in vitro . Chemical inhibitors such as dorsomorphin 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 (R206H and G356D) 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. Takahashi M et al. PNAS 2010;107(50):21731–6; Takahashi M et al. Gene Therapy 2011, in press.