Splice-region antisense composition and method
First Claim
1. An antisense compound having an uncharged morpholino backbone and a base sequence between 12 and 25 nucleotide bases in length which is complementary to a target region of a selected preprocessed mRNA coding for a protein selected from the group consisting of myc, myb, rel, fos, jun, ab1, bc1, p53, an integrin, a cathedrin, a telomerase, a cytokine, a kinase, a receptor protein, hCG, HIV rev, human papilloma virus, and human parvovirus B19, where the 5′
- end of the target region is 1-25 bases downstream of a normal splice acceptor site in said preprocessed mRNA.
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Abstract
Antisense compositions targeted against an mRNA sequence coding for a selected protein, at a region having its 5′ end from 1 to about 25 base pairs downstream of a normal splice acceptor junction in the preprocessed mRNA, are disclosed. The antisense compound is RNase-inactive, and is preferably a phosphorodiamidate-linked morpholino oligonucleotide. Such targeting is effective to inhibit natural mRNA splice processing, produce splice variant mRNAs, and inhibit normal expression of the protein.
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Citations
38 Claims
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1. An antisense compound having an uncharged morpholino backbone and a base sequence between 12 and 25 nucleotide bases in length which is complementary to a target region of a selected preprocessed mRNA coding for a protein selected from the group consisting of myc, myb, rel, fos, jun, ab1, bc1, p53, an integrin, a cathedrin, a telomerase, a cytokine, a kinase, a receptor protein, hCG, HIV rev, human papilloma virus, and human parvovirus B19,
where the 5′ - end of the target region is 1-25 bases downstream of a normal splice acceptor site in said preprocessed mRNA.
- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22)
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23. A method of inhibiting normal splicing of mRNA in a eukaryotic cell, comprising
contacting the cell with an antisense compound having an uncharged morpholino backbone and a base sequence between 12 and 25 nucleotide bases in length which is complementary to a target region of a selected preprocessed mRNA coding for a selected protein; - where the 5′
end of the target region is 1-25 bases downstream of the a normal splice acceptor site in said preprocessed mRNA,wherein the compound;
is taken up by the cell;
hybridizes to the target region of preprocessed mRNA in the cell, and being so hybridized, prevents splicing at said normal acceptor splice site, such that the splice mechanism proceeds to a downstream splice acceptor sequence in the mRNA, producing a splice variant processed mRNA with a truncated coding sequence. - View Dependent Claims (24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38)
- where the 5′
Specification