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J Biol Chem, Vol. 274, Issue 51, 36193-36199, December 17, 1999
From the Departments of The CFTR splicing mutation 3849 + 10 kb C
Correction of Aberrant Splicing of the Cystic Fibrosis
Transmembrane Conductance Regulator (CFTR) Gene by
Antisense Oligonucleotides*
,
,, and
Pathology and Laboratory
Medicine, Medicine, and ** Pharmacology and the Lineberger
Comprehensive Cancer Center, University of North Carolina, Chapel Hill,
North Carolina 27599 and § Department of Medicine, Duke
University Medical Center and the ¶ Veterans Affairs Medical
Center, Durham, North Carolina 27710
T creates a novel donor site 10 kilobases (kb) into intron 19 of the gene and is one of the more common splicing mutations that
causes cystic fibrosis (CF). It has an elevated prevalence among
patients with atypically mild disease and normal sweat electrolytes and
is especially prominent in Ashkenazi Jews. This class of splicing
mutations, reported in several genes, involves novel splice sites
activated deep within introns while leaving wild-type splice elements
intact. CFTR cDNA constructs that modeled the 3849 + 10 kb C T mutation were expressed in 3T3 mouse fibroblasts and in CFT1
human tracheal and C127 mouse mammary epithelial cells. In all three
cell types, aberrant splicing of CFTR pre-mRNA was comparable to
that reported in vivo in CF patients. Treatment of the
cells with 2'-O-methyl phosphorothioate
oligoribonucleotides antisense toward the aberrant donor and acceptor
splice sites or to the retained exon-like sequence, disfavored aberrant
splicing and enhanced normal processing of CFTR pre-mRNA. This
antisense-mediated correction of splicing was dose- and
sequence-dependent and was accompanied by increased production of CFTR protein that was appropriately glycosylated. Antisense-mediated correction of splicing in a mutation-specific context represents a potential gene therapy modality with applicability to many inherited disorders.
*
This work was supported in part by grants from the Cystic
Fibrosis Foundation, the National Institutes of Health, and the Veteran's Administration.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom all correspondence and reprint requests should be
addressed: University of North Carolina, Lineberger Comprehensive Cancer Center, CB7295, Chapel Hill, NC 27599. Tel.: 919-966-1143; Fax:
919-966-3015; E-mail: kole@med.unc.edu.
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