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 in vivo or in vitro method for inducing ubiquitin-protein ligase E3A (UBE3A) expression in a target cell where expression of paternal UBE3A is suppressed, said method comprising administering an oligonucleotide consisting of 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, in an effective amount to said cell.
2. The method according to claim 1 , wherein the expression of UBE3A is increased by at least 40% compared to a control.
3. The method according to claim 1 , wherein the level of SNHG14 transcript downstream of SNORD109B is reduced by at least 30% compared to a control.
4. The method according to claim 1 , wherein the target cell is a neuronal cell.
5. The method according to claim 2 , wherein the target cell is a neuronal cell.
6. The method according to claim 3 , wherein the target cell is a neuronal cell.
7. The method of claim 1 , wherein the expression of SNORD115 is not significantly affected compared to a control.
8. A method for treating a disease comprising administering a therapeutically effective amount of an oligonucleotide consisting of 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 to a subject suffering from or susceptible to Angelman syndrome.
9. A method for treating Angelman syndrome comprising administering a therapeutically effective amount of an oligonucleotide consisting of 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 to a subject suffering from or susceptible to Angelman syndrome.