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Restoration of normal BMP signaling levels and osteogenic differentiation in FOP mesenchymal progenitor cells by mutant allele-specific targeting

Gene Therapy volume 19, pages 786–790 (2012)Cite this article

Abstract

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.

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Acknowledgements

We thank the members of our research laboratory for their helpful discussions during the development of these studies. This work was supported in part by the Center for Research in FOP and Related Disorders, the International FOP Association (IFOPA), the Ian Cali Endowment, the Weldon Family Endowment, the Isaac and Rose Nassau Professorship of Orthopaedic Molecular Medicine, the Rita Allen Foundation, and the Penn Musculoskeletal Center, and by grants from the NIH (R01-AR41916 and R01-AR046831).

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Authors and Affiliations

  1. Department of Orthopaedic Surgery, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA

    J Kaplan, F S Kaplan & E M Shore

  2. Department of Medicine, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA

    J Kaplan, F S Kaplan & E M Shore

  3. Department of Genetics, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA

    F S Kaplan

  4. Centre of Research in FOP and Related Disorders, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA

    E M Shore

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  1. J Kaplan
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Correspondence to E M Shore.

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Supplementary Information accompanies the paper on Gene Therapy website

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Kaplan, J., Kaplan, F. & Shore, E. Restoration of normal BMP signaling levels and osteogenic differentiation in FOP mesenchymal progenitor cells by mutant allele-specific targeting. Gene Ther 19, 786–790 (2012). https://doi.org/10.1038/gt.2011.152

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