Antisense compounds targeting genes associated with usher syndrome
The present invention provides compounds comprising oligonucleotides complementary to an Usher transcript. Certain such compounds are useful for hybridizing to an Usher transcript, including but not limited, to an Usher transcript in a cell. In certain embodiments, such hybridization results in modulation of splicing of the Usher transcript. In certain such embodiments, the Usher transcript includes a mutation that results in cryptic splicing and hybridization of the oligonucleotide results in a decrease in the amount of cryptic splicing. In certain embodiments, such compounds are used to treat Usher Syndrome.
1. A compound comprising a modified oligonucleotide consisting of 15 to 24 linked nucleosides and having a nucleobase sequence comprising a complementary region comprising at least 15 contiguous nucleobases complementary to a target region of equal length within exon 3 or intron 3 of an Usher transcript, wherein the Usher transcript has the nucleobase sequence of SEQ ID NO.: 1, and wherein the complementary region of the modified oligonucleotide is 100% complementary to the target region and comprises 10 contiguous nucleobases of SEQ ID NO: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 24, 25, 26, 28, 29, 30, 31, 49, 50, 51, 52, 53, 54, 55, 56, 57, or 58.
2. The compound of claim 1 , wherein the nucleobase sequence of the oligonucleotide is 100% complementary to an equal-length region within exon 3 or intron 3 of the Usher transcript, as measured over the entire length of the oligonucleotide.
3. The compound of claim 1 , wherein the modified oligonucleotide comprises at least one modified nucleoside.
4. The compound of claim 3 , wherein at least one modified nucleoside comprises a modified sugar moiety.
5. The compound of claim 4 , wherein at least one modified sugar moiety is a 2′-substituted sugar moiety.
6. The compound of claim 5 , wherein the 2′-substitutent of at least one 2′-substituted sugar moiety is selected from among: 2′-OMe, 2′-F, and 2′-MOE.
7. The compound of claim 6 , wherein the 2′-substitutent of at least one 2′-substituted sugar moiety is 2′-MOE.
8. The compound of claim 1 , wherein the modified oligonucleotide comprises at least 15 modified nucleosides.
9. The compound of claim 8 , wherein each modified nucleoside comprises a modified sugar moiety.
10. The compound of claim 9 , wherein at least one modified sugar moiety is a 2′-substituted sugar moiety.
11. The compound of claim 10 , wherein the 2′-substitutent of at least one 2′-substituted sugar moiety is selected from among: 2′-OMe, 2′-F, and 2′-MOE.
12. The compound of claim 11 , wherein the 2′-substitutent of at least one 2′-substituted sugar moiety is 2′-MOE.
13. The compound of claim 1 , wherein at least one internucleoside linkage of the modified oligonucleotide is a modified internucleoside linkage and wherein each internucleoside linkage comprises the same modification.
14. The compound of claim 13 , wherein each internucleoside linkage is a phosphorothioate internucleoside linkage.
15. The compound of claim 1 , wherein the modified oligonucleotide has a nucleobase sequence selected from among SEQ ID NOs. 30, 19, 20, 21, 22, 24, 25, 26, 28, or 29.