Restoration of normal BMP signaling levels and osteogenic differentiation in FOP mesenchymal progenitor cells by mutant allele-specific targeting.
Gene Ther
; 19(7): 786-90, 2012 Jul.
Article
en En
| MEDLINE
| ID: mdl-22011642
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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Osteogénesis
/
Diferenciación Celular
/
Silenciador del Gen
/
Receptores de Activinas Tipo I
/
ARN Interferente Pequeño
/
Células Madre Mesenquimatosas
/
Miositis Osificante
Límite:
Humans
Idioma:
En
Revista:
Gene Ther
Asunto de la revista:
GENETICA MEDICA
/
TERAPEUTICA
Año:
2012
Tipo del documento:
Article
País de afiliación:
Estados Unidos
Pais de publicación:
Reino Unido