Splice-region antisense composition and method
View Patent ↗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.
1. An oligomer of 8 to 40 morpholino subunits connected by phosphorous-containing intersubunit linkages, wherein the 5′ terminal morpholino subunit comprises a group of the formula:
wherein each R 1 is independently a C 1 -C 6 alkyl.
2. The oligomer of claim 1 , wherein the 5′ terminal morpholino subunit is of a formula:
wherein each P is independently a purine or pyrimidine base-pairing moiety.
3. The oligomer of claim 1 , wherein the oligomer is of a formula:
or a pharmaceutically acceptable salt thereof,
wherein:
each R 1 is independently a C 1 -C 6 alkyl;
each P is independently a purine or pyrimidine base-pairing moiety;
X is an integer from 3 to 19; and
R 3 is selected from H and trityl.
4. The oligomer of claim 1 , wherein each R 1 is independently selected from methyl, ethyl, isopropyl, n-butyl, isobutyl, and t-butyl.
5. The oligomer of claim 3 , wherein each R 1 is methyl.
6. The oligomer of claim 3 , wherein R 3 is H.
7. The oligomer of claim 3 , wherein each R 1 is methyl, and R 3 is H.
8. The oligomer of claim 3 , wherein each P is independently selected from adenine, cytosine, guanine, uracil, and thymine.
9. A compound of formula:
or a pharmaceutically acceptable salt thereof, wherein X is an integer from 3 to 19, and each P is independently a purine or pyrimidine base-pairing moiety selected from adenine, cytosine, guanine, uracil, and thymine.
10. The oligomer of claim 1 , wherein the oligomer is of a formula:
or a pharmaceutically acceptable salt thereof,
wherein:
each R 1 is independently a C 1 -C 6 alkyl;
each P is independently a purine or pyrimidine base-pairing moiety;
X is an integer from 6 to 38; and
R 3 is selected from H and trityl.
11. The oligomer of claim 10 , wherein each R 1 is independently selected from methyl, ethyl, isopropyl, n-butyl, isobutyl, and t-butyl.
12. The oligomer of claim 10 , wherein each R 1 is methyl.
13. The oligomer of claim 10 , wherein R 3 is H.
14. The oligomer of claim 10 , wherein each R 1 is methyl, and R 3 is H.
15. The oligomer of claim 10 , wherein each P is independently selected from adenine, cytosine, guanine, uracil, and thymine.
16. A compound of formula:
or a pharmaceutically acceptable salt thereof, wherein X is an integer from 6 to 38, and each P is independently a purine or pyrimidine base-pairing moiety selected from adenine, cytosine, guanine, uracil, and thymine.