TY - JOUR
T1 - Antisense-induced messenger depletion corrects a COL6A2 dominant mutation in ullrich myopathy
AU - Gualandi, Francesca
AU - Manzati, Elisa
AU - Sabatelli, Patrizia
AU - Passarelli, Chiara
AU - Bovolenta, Matteo
AU - Pellegrini, Camilla
AU - Perrone, Daniela
AU - Squarzoni, Stefano
AU - Pegoraro, Elena
AU - Bonaldo, Paolo
AU - Ferlini, Alessandra
PY - 2012/12/1
Y1 - 2012/12/1
N2 - Collagen VI gene mutations cause Ullrich and Bethlem muscular dystrophies. Pathogenic mutations frequently have a dominant negative effect, with defects in collagen VI chain secretion and assembly. It is agreed that, conversely, collagen VI haploinsufficiency has no pathological consequences. Thus, RNA-targeting approaches aimed at preferentially inactivating the mutated COL6 messenger may represent a promising therapeutic strategy. By in vitro studies we obtained the preferential depletion of the mutated COL6A2 messenger, by targeting a common single-nucleotide polymorphism (SNP), cistronic with a dominant COL6A2 mutation. We used a 2′-O-methyl phosphorothioate (2′OMePS) antisense oligonucleotide covering the SNP within exon 3, which is out of frame. Exon 3 skipping has the effect of depleting the mutated transcript via RNA nonsense-mediated decay, recovering the correct collagen VI secretion and restoring the ability to form an interconnected microfilament network into the extracellular matrix. This novel RNA modulation approach to correcting dominant mutations may represent a therapeutic strategy potentially applicable to a great variety of mutations and diseases.
AB - Collagen VI gene mutations cause Ullrich and Bethlem muscular dystrophies. Pathogenic mutations frequently have a dominant negative effect, with defects in collagen VI chain secretion and assembly. It is agreed that, conversely, collagen VI haploinsufficiency has no pathological consequences. Thus, RNA-targeting approaches aimed at preferentially inactivating the mutated COL6 messenger may represent a promising therapeutic strategy. By in vitro studies we obtained the preferential depletion of the mutated COL6A2 messenger, by targeting a common single-nucleotide polymorphism (SNP), cistronic with a dominant COL6A2 mutation. We used a 2′-O-methyl phosphorothioate (2′OMePS) antisense oligonucleotide covering the SNP within exon 3, which is out of frame. Exon 3 skipping has the effect of depleting the mutated transcript via RNA nonsense-mediated decay, recovering the correct collagen VI secretion and restoring the ability to form an interconnected microfilament network into the extracellular matrix. This novel RNA modulation approach to correcting dominant mutations may represent a therapeutic strategy potentially applicable to a great variety of mutations and diseases.
UR - http://www.scopus.com/inward/record.url?scp=84871191947&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84871191947&partnerID=8YFLogxK
U2 - 10.1089/hum.2012.109
DO - 10.1089/hum.2012.109
M3 - Article
C2 - 22992134
AN - SCOPUS:84871191947
VL - 23
SP - 1313
EP - 1318
JO - Human Gene Therapy
JF - Human Gene Therapy
SN - 1043-0342
IS - 12
ER -