Compounds and methods for modulating UBE3A-ATS
Provided are compounds, methods, and pharmaceutical compositions for reducing the amount or activity of UBE3A-ATS, the endogenous antisense transcript of ubiquitin protein ligase E3A (UBE3A) in a cell or subject, and in certain instances increasing the expression of paternal UBE3A and the amount of UBE3A protein in a cell or subject. Such compounds, methods, and pharmaceutical compositions are useful to ameliorate at least one symptom or hallmark of a neurogenetic disorder. Such symptoms and hallmarks include developmental delays, ataxia, speech impairment, sleep problems, seizures, and EEG abnormalities. Such neurogenetic disorders include Angelman Syndrome.
1. A modified oligonucleotide according to the following chemical structure:
or a salt thereof.
2. The modified oligonucleotide of claim 1 , which is the sodium salt or the potassium salt.
3. A modified oligonucleotide according to the following chemical structure:
4. A pharmaceutical composition comprising the modified oligonucleotide of claim 1 and a pharmaceutically acceptable diluent.
5. The pharmaceutical composition of claim 4 , wherein the pharmaceutically acceptable diluent is artificial cerebrospinal fluid.
6. The pharmaceutical composition of claim 5 , wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and artificial cerebrospinal fluid.
7. A pharmaceutical composition comprising the modified oligonucleotide of claim 3 and a pharmaceutically acceptable diluent.
8. The pharmaceutical composition of claim 7 , wherein the pharmaceutically acceptable diluent is artificial cerebrospinal fluid.
9. The pharmaceutical composition of claim 8 , wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and artificial cerebrospinal fluid.
10. A compound comprising a modified oligonucleotide according to the following chemical notation:
A es m C eo m C eo A eo T eo T ds T ds T ds G ds A ds m C ds m C ds T ds T ds m C ds T eo T eo A es G es m C e (SEQ ID NO: 2873), wherein:
A=an adenine nucleobase,
m C=a 5-methyl cytosine nucleobase,
G=a guanine nucleobase,
T=a thymine nucleobase,
e=a 2′—O(CH 2 ) 2 OCH 3 β-D-ribosyl sugar moiety,
d=a 2′-β-D-deoxyribosyl sugar moiety,
s=a phosphorothioate internucleoside linkage, and
o=a phosphodiester internucleoside linkage.
11. A pharmaceutical composition comprising a compound of claim 10 , and a pharmaceutically acceptable diluent.
12. The pharmaceutical composition of claim 11 , wherein the pharmaceutically acceptable diluent is artificial cerebrospinal fluid.
13. The pharmaceutical composition of claim 12 , wherein the pharmaceutical composition consists essentially of the compound and artificial cerebrospinal fluid.
14. The compound of claim 10 , comprising the modified oligonucleotide covalently linked to a conjugate group.
15. A pharmaceutical composition comprising a compound of claim 14 , and a pharmaceutically acceptable diluent.
16. The pharmaceutical composition of claim 15 , wherein the pharmaceutically acceptable diluent is artificial cerebrospinal fluid.
17. The pharmaceutical composition of claim 16 , wherein the pharmaceutical composition consists essentially of the compound and artificial cerebrospinal fluid.