Oligonucleotides for inducing paternal UBE3A expression
The present invention relates to oligonucleotides that are capable of inducing expression of ubiquitin-protein ligase E3A (UBE3A) from the paternal allele in animal or human neurons. The oligonucleotides target the suppressor of the UBE3A paternal allele by hybridization to SNHG14 long non-coding RNA downstream of SNORD109B. The present invention further relates to pharmaceutical compositions and methods for treatment of Angelman syndrome.
1. An antisense oligonucleotide which is the oligonucleotide compound AAtTaTttatacacCATcAT (SEQ ID NO: 585), wherein capital letters represent beta-D-oxy LNA nucleosides, lowercase letters represent DNA nucleosides, all LNA C are 5-methyl cytosine, and all internucleoside linkages are phosphorothioate internucleoside linkages.
2. A conjugate comprising the oligonucleotide of claim 1 , and at least one conjugate moiety covalently attached to said oligonucleotide.
3. A pharmaceutical composition comprising the oligonucleotide of claim 1 and a pharmaceutically acceptable diluent, solvent, carrier, salt and/or adjuvant.
4. The pharmaceutical composition of claim 3 , wherein the pharmaceutically acceptable salt is a sodium salt.
5. The pharmaceutical composition of claim 3 , wherein the pharmaceutically acceptable salt is a potassium salt.
6. An in vitro method for inducing ubiquitin-protein ligase E3A (UBE3A) expression in a target cell where expression of paternal UBE3A is suppressed, the method comprising administering an oligonucleotide of claim 1 in an effective amount to said cell.
7. The method of to claim 6 , wherein the target cell is a neuronal cell.
8. The method of claim 6 wherein the expression of SNORD115 is not significantly affected compared to a control.
9. A method for treating Angelman syndrome comprising administering a prophylactically effective amount of the oligonucleotide of claim 1 to a subject suffering from or susceptible to Angelman syndrome.
10. A method for treating Angelman syndrome comprising administering a therapeutically effective amount of the oligonucleotide of claim 1 to a subject suffering from or susceptible to Angelman syndrome.
11. A pharmaceutically acceptable salt of the antisense oligonucleotide of claim 1 .
12. The pharmaceutical composition according to claim 3 wherein the pharmaceutically acceptable diluent includes phosphate-buffered saline (PBS).
13. The method according to claim 6 , wherein the expression of UBE3A is increased by at least 40% compared to a control.
14. The method according to claim 13 , wherein the level of the SNHG14 transcript downstream of SNORD109B is reduced by at least 30% compared to a control.
15. A pharmaceutically acceptable sodium salt of the antisense oligonucleotide of claim 1 .
16. A pharmaceutically acceptable potassium salt of the antisense oligonucleotide of claim 1 .