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. A pharmaceutically acceptable salt of an antisense oligonucleotide wherein the oligonucleotide is the oligonucleotide compound TTAcActtaattatactTCC (SEQ ID NO: 626), 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. The pharmaceutically acceptable salt of claim 1 , wherein the pharmaceutically acceptable salt is a sodium salt.
3. The pharmaceutically acceptable salt of claim 1 , wherein the pharmaceutically acceptable salt is a potassium salt.
4. A pharmaceutical composition comprising the pharmaceutically acceptable salt of claim 1 and a pharmaceutically acceptable diluent, solvent, carrier and/or adjuvant.
5. The pharmaceutical composition according to claim 4 , wherein the pharmaceutically acceptable diluent includes phosphate-buffered saline (PBS).
6. An in vitro or in vivo method for inducing ubiquitin-protein ligase E3A (UBE3A) expression in a target cell where expression of paternal UBE3A is suppressed, said method comprising administering the pharmaceutically acceptable salt of claim 1 in an effective amount to said cell.
7. The method according to claim 6 , wherein the expression of UBE3A is increased by at least 40% compared to a control.
8. The method according to claim 6 , wherein the level of the SNHG14 transcript downstream of SNORD109B is reduced by at least 30% compared to a control.
9. The method according to claim 6 wherein the target cell is a neuronal cell.
10. A method for treating Angelman syndrome comprising administering a prophylactically effective amount of the pharmaceutically acceptable salt of claim 1 to a subject suffering from or susceptible to Angelman syndrome.
11. A method for treating Angelman syndrome comprising administering a therapeutically effective amount of the pharmaceutically acceptable salt of claim 1 to a subject suffering from or susceptible to Angelman syndrome.