Journal
GENE THERAPY
Volume 19, Issue 7, Pages 786-790Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/gt.2011.152
Keywords
Allele-specific RNAi; fibrodysplasia ossificans progressiva; FOP; heterotopic ossification; bone morphogenetic protein; ACVR1/ALK2
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Funding
- Center for Research in FOP and Related Disorders
- International FOP Association (IFOPA)
- Ian Cali Endowment
- Weldon Family Endowment
- Isaac and Rose Nassau Professorship of Orthopaedic Molecular Medicine
- Rita Allen Foundation
- Penn Musculoskeletal Center
- NIH [R01-AR41916, R01-AR046831]
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Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder of progressive heterotopic ossification for which there is presently no cure. FOP is caused by a recurrent heterozygous activating mutation (c.617G>A; R206H) of Activin receptor type IA/Activin-like kinase-2 (ACVR1/ALK2), a bone morphogenetic protein (BMP) type I receptor that occurs in all classically affected individuals. The FOP mutation dysregulates BMP signaling and initiates the formation of a disabling second skeleton of heterotopic bone. We generated allele-specific siRNA (ASP-RNAi) duplexes capable of specifically suppressing the expression of the mutant c.617A allele in mesenchymal progenitor cells from FOP patients and showed that this ASP-RNAi approach 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. Our results provide proof-of-principle that ASP-RNAi has potential therapeutic efficacy for the treatment of FOP. Gene Therapy (2012) 19, 786-790; doi:10.1038/gt.2011.152; published online 20 October 2011
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