Modulation of pre-mRNA using splice modulating oligonucleotides as therapeutic agents in the treatment of disease
The present invention encompasses a class of compounds known as splice modulating oligonucleotides (SMOs) that modulate pre-mRNA splicing, thereby affecting expression and functionality of a specific protein in a cell. The present invention further provides compositions and methods for modulating pre-mRNA splicing using a SMO of the invention to abrogate disease-causing mutations in a protein. Accordingly, the present invention provides compositions and methods of treating a subject at risk of, susceptible to, or having a disease, disorder, or condition associated with aberrant or unwanted target pre-mRNA expression or activity.
1. A composition comprising a splice modulating oligonucleotide (SMO) that specifically binds a complementary sequence of a pre-mRNA that undergoes splicing to form a mRNA encoding a glutamate activated α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit (GluR), wherein said SMO is selected from any of SEQ ID NOs: 86, 123, 143, 228, 243, 269, 306, 318, 442, or 496, or a sequence having at least 90% identity over the full sequence of any of SEQ ID NOs: 86, 123, 143, 228, 243, 269, 306, 318, 442, or 496.
2. The composition according to claim 1 , wherein at least one nucleotide in said SMO contains a non-naturally occurring modification comprising at least one of a chemical composition of phosphorothioate 2′-O-methyl, phosphorothioate 2′-MOE, locked nucleic acid (LNA), peptide nucleic acid (PNA), phosphorodiamidate morpholino, or any combination thereof.
3. The composition according to claim 1 , further comprising a pharmaceutically acceptable carrier.
4. A composition according to claim 1 , wherein said SMO is a sequence having at least 95% identity over the full sequence of any of SEQ ID NOs: 86, 123, 143, 228, 243, 269, 306, 318, 442, or 496.
5. A composition according to claim 4 , wherein said SMO is selected from any of SEQ ID NOs: 86, 123, 143, 228, 243, 269, 306, 318, 442, or 496.
6. The composition according to claim 1 , wherein said SMO is a sequence having at least 90% identity over the full sequence of SEQ ID NO: 123.
7. The composition according to claim 1 , wherein said SMO is a sequence having at least 90% identity over the full sequence of SEQ ID NO: 243.
8. The composition according to claim 1 , wherein said SMO is a sequence having at least 90% identity over the full sequence of SEQ ID NO: 269.
9. The composition according to claim 1 , wherein said SMO is a sequence having at least 90% identity over the full sequence of SEQ ID NO: 306.
10. The composition according to claim 1 , wherein said SMO is a sequence having at least 90% identity over the full sequence of SEQ ID NO: 318.
11. The composition according to claim 1 , wherein said SMO is a sequence having at least 90% identity over the full sequence of SEQ ID NO: 442.
12. The composition according to claim 1 , wherein said SMO is a sequence having at least 90% identity over the full sequence of SEQ ID NO: 496.
13. A composition comprising a splice modulating oligonucleotide (SMO) that specifically binds a complementary sequence of a pre-mRNA that undergoes splicing to form a mRNA encoding a glutamate activated α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit (GluR), wherein said SMO is SEQ ID NO: 228, or a sequence having at least 90% identity over the full sequence of SEQ ID NO: 228.
14. The composition according to claim 13 , wherein said SMO is a sequence having at least 95% identity over the full sequence of SEQ ID NO: 228.
15. The composition according to claim 14 , wherein said SMO is SEQ ID NO: 228.
16. A composition comprising a splice modulating oligonucleotide (SMO) that specifically binds a complementary sequence of a pre-mRNA that undergoes splicing to form a mRNA encoding a glutamate activated α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit (GluR), wherein said SMO is SEQ ID NO: 86 or 143, or a sequence having at least 90% identity over the full sequence of SEQ ID NO: 86 or 143.
17. The composition according to claim 16 , wherein said SMO is a sequence having at least 95% identity over the full sequence of SEQ ID NO: 86.
18. The composition according to claim 17 , wherein said SMO is SEQ ID NO: 86.
19. The composition according to claim 16 , wherein said SMO is a sequence having at least 95% identity over the full sequence of SEQ ID NO: 143.
20. The composition according to claim 19 , wherein said SMO is SEQ ID NO: 143.