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1. WO2020115106 - ANTISENSE OLIGONUCLEOTIDES RESCUE ABERRANT SPLICING OF ABCA4

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[ EN ]
Claims

1. An antisense oligonucleotide for redirecting splicing that binds to and/or is complementary to a polynucleotide with the nucleotide sequence as shown in SEQ ID NO: 4, preferably the antisense oligonucleotide binds to or is complementary to a polynucleotide with SEQ ID NO: 5, more preferably the antisense oligonucleotide binds to or is complementary to a polynucleotide with SEQ ID NO: 80, even more preferably the antisense oligonucleotide binds to or is complementary to a polynucleotide selected from the group consisting of SEQ ID NO: 7, 8, 9; 11 , 12,13; 15,16,17; 19, 20, and 21.

2. An antisense oligonucleotide for redirecting splicing according to claim 1 , wherein a nucleotide in the antisense oligonucleotide may be an RNA residue, a DNA residue, or a nucleotide analogue or equivalent.

3. An antisense oligonucleotide for redirecting splicing according to claim 1 , wherein the antisense oligonucleotide has a length of from about 8 to about 40 nucleotides, preferably from about 10 to about 40 nucleotides, more preferably from about 14 to about 30 nucleotides, more preferably from about 16 to about 24 nucleotides, such as 16, 17, 18, 19, 20, 21 , 22, 23 or 24 nucleotides.

4. An antisense oligonucleotide for redirecting splicing according to any one of the proceeding claims, wherein the antisense oligonucleotide comprises or consists of SEQ ID NO: 34, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 73, 75 or 77.

5. An antisense oligonucleotide for redirecting splicing according any one of claims 1-3, comprising a 2'-0 alkyl phosphorothioate antisense oligonucleotide, such as 2'-0-methyl modified ribose (RNA), 2'-0-ethyl modified ribose, 2'-0-methoxyethyl modified ribose, 2'-0-propyl modified ribose, and/or substituted derivatives of these modifications such as halogenated derivatives.

6. An antisense oligonucleotide for redirecting splicing according to any one of the preceding claims, wherein the antisense oligonucleotide comprises or consists of SEQ ID NO: 34, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 73, 75 or 77, and wherein the antisense oligonucleotide comprises a 2'-0-methyl modified ribose (RNA) or a 2'-0-methoxyethyl modified ribose and a phosphorothioate backbone.

7. A viral vector expressing antisense oligonucleotide for redirecting splicing as defined in any one of claims 1-4 when placed under conditions conducive to expression of the molecule.

8. A pharmaceutical composition comprising an antisense oligonucleotide for redirecting splicing according to any one of claims 1-4 or a viral vector according to claim 7 and a pharmaceutically acceptable excipient.

9. A pharmaceutical composition according to claim 8, wherein the pharmaceutical composition is for intravitreal administration and is dosed in an amount ranged from 0.05 mg and 5 mg of total antisense oligonucleotides.

10. A pharmaceutical composition according to claims 8 and 9, wherein the pharmaceutical composition is for intravitreal administration and is dosed in an amount ranged from 0.1 and 1 mg of total antisense oligonucleotides for redirecting splicing per eye, such as about 0.1 , 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 or 1.0 mg of total antisense oligonucleotides for redirecting splicing per eye.

11. The antisense oligonucleotide for redirecting splicing according to any one of claims 1-4, the vector according to claim 7 or the pharmaceutical composition according to any one of claims 8-10 for use as a medicament, preferably for use as a medicament for treating an ABCA4 related disease or a condition requiring modulating splicing of ABCA4.

12. Use of the antisense oligonucleotide for redirecting splicing according to claims 1-4, the vector according to claim 7 or the pharmaceutical composition according to any one of claims 8-10 for treating an ABCA4 related disease or a condition requiring modulating splicing of ABCA4.

13. A method for modulating splicing of ABCA4 in a cell, said method comprising contacting said cell with an antisense oligonucleotide for redirecting splicing as defined in any one of claims 1-4, the vector according to claim 7 or the pharmaceutical composition according to any one of claims 8 10

14. The antisense oligonucleotide for redirecting splicing for use according to claim 11 , the use according to claim 12 or the method according to claim 13, wherein the ABCA4-related disease or condition is Stargardt disease.