Antisense oligonucleotides which combat aberrant splicing and methods of using the same
First Claim
1. A method of combatting alternate splicing in a pre-mRNA molecule:
- wherein said pre-mRNA molecule contains a first set of splice elements defining a first intron which is removed by splicing to produce a first mRNA molecule encoding a first protein;
and wherein said pre-mRNA further contains a second set of splice elements defining an alternate intron different from said first intron, which alternate intron is removed by splicing to produce an alternate second mRNA molecule different from said first mRNA molecule;
said method comprising;
hybridizing an antisense oligonucleotide to said pre-mRNA molecule to create a duplex molecule under conditions which permit splicing,wherein said antisense oligonucleotide does not activate RNase H;
and wherein said oligonucleotide blocks a member of said alternate second set of splice elements;
so that said first intron is removed by splicing and said first mRNA molecule encoding a protein is produced.
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Abstract
A method of combatting aberrant splicing in a pre-mRNA molecule containing a mutation is disclosed. When present in the pre-mRNA, the mutation causes the pre-mRNA to splice incorrectly and produce an aberrant mRNA or mRNA fragment different from the mRNA ordinarily encoded by the pre-mRNA. The method comprises hybridizing an antisense oligonucleotide to the pre-mRNA molecule to create a duplex molecule under conditions which permit splicing. The antisense oligonucleotide is one which does not activate RNase H, and is selected to block a member of the aberrant set of splice elements created by the mutation so that the native intron is removed by splicing and the first mRNA molecule encoding a native protein is produced. Oligonucleotides useful for carrying out the method are also disclosed.
164 Citations
13 Claims
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1. A method of combatting alternate splicing in a pre-mRNA molecule:
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wherein said pre-mRNA molecule contains a first set of splice elements defining a first intron which is removed by splicing to produce a first mRNA molecule encoding a first protein; and wherein said pre-mRNA further contains a second set of splice elements defining an alternate intron different from said first intron, which alternate intron is removed by splicing to produce an alternate second mRNA molecule different from said first mRNA molecule; said method comprising; hybridizing an antisense oligonucleotide to said pre-mRNA molecule to create a duplex molecule under conditions which permit splicing, wherein said antisense oligonucleotide does not activate RNase H; and wherein said oligonucleotide blocks a member of said alternate second set of splice elements; so that said first intron is removed by splicing and said first mRNA molecule encoding a protein is produced. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13)
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Specification