Inhibition of polyomavirus replication

Patent metadata

Field	Value
Publication number	US-12480122-B2
Application number	US-202217846457-A
Country	US
Kind code	B2
Filing date	Jun 22, 2022
Priority date	Mar 2, 2018
Publication date	Nov 25, 2025
Grant date	Nov 25, 2025

Abstract

The invention relates to antisense molecules and methods for modulating splicing of polyomavirus T antigen pre-mRNA. In one aspect the invention relates to an antisense oligonucleotide 12 to 30, preferably 17, 18, 19 or 20 to 30 nucleobases in length which comprises a sequence that is the reverse complement of a contiguous stretch of at least 12 nucleobases of a polyomavirus T-antigen pre-mRNA and which antisense oligonucleotide can modulate splicing of said T-antigen pre-mRNA in a cell.

First claim

The invention claimed is:

1 . A single stranded (ss) RNA antisense oligonucleotide of 18 to 30 ribonucleotides in length comprising a sequence that is a reverse complement of a contiguous stretch of at least 18 nucleobases of a polyomavirus T-antigen pre-mRNA, wherein the ssRNA antisense oligonucleotide comprises a modification capable of rendering an RNA duplex resistant to the action of RNase H, wherein the RNA duplex is formed by the ssRNA antisense oligonucleotide and the T-antigen pre-mRNA, wherein the ssRNA antisense oligonucleotide is capable of modulating splicing of said T-antigen pre-mRNA in a cell, and wherein the ssRNA antisense oligonucleotide is directed towards the splice donor site of exon 1, wherein the oligonucleotide comprises one or more nucleobases targeting exon 1 and one or more nucleobases targeting the corresponding intronic region of said splice donor at exon 1.

2 . The ssRNA antisense oligonucleotide of claim 1 , comprising at least 18 contiguous nucleobases of the sequence of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, or a variant thereof, wherein the variant comprises one or more substitutions by a nucleobase analogue having the same base pairing specificity as the replaced nucleobase.

3 . The ssRNA antisense oligonucleotide of claim 1 , wherein the modification comprises a 2′ sugar modification.

4 . The ssRNA antisense oligonucleotide of claim 3 , wherein the 2′ sugar modification is a 2′-alkoxy, a 2′-alkoxyalkoxy, a 2′-O-methyl (2′-O-Me), a 2′-O-methoxyethyl (2′-MOE), a 2′-S-constrained-ethyl (2′-cEt), or a locked nucleic acid (LNA) modification.

5 . The ssRNA antisense oligonucleotide of claim 1 , further comprising at least one backbone modification.

6 . The ssRNA antisense oligonucleotide of claim 5 , wherein the at least one backbone modification is a phosphorothioate, a 2′-O-methyl (2′-O-Me), a 2′-O-methoxyethyl (2′-MOE), a 2′-S-constrained-ethyl (2′-cEt), a locked nucleic acid (LNA), a peptide nucleic acid (PNA), or a morpholino (PMO) modification.

7 . The ssRNA antisense oligonucleotide of claim 1 , comprising at least 18 contiguous nucleobases of the sequence of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, or a variant thereof having one nucleobase substitution between the first and the last nucleobase of the at least 18 contiguous nucleobases by a nucleobase analogue having the same base pairing specificity as the replaced nucleobase.

8 . The ssRNA antisense oligonucleotide of claim 1 , comprising at least 18 contiguous nucleobases of the sequence of SEQ ID NO: 3, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, or a variant thereof, wherein the variant comprises one or more substitutions by a nucleobase analogue having the same base pairing specificity as the replaced nucleobase.

9 . The ssRNA antisense oligonucleotide of claim 1 , comprising at least 1 contiguous nucleobases of the sequence of SEQ ID NO: 23, SEQ ID NO: 24, or a variant thereof, wherein the variant comprises one or more substitutions by a nucleobase analogue having the same base pairing specificity as the replaced nucleobase.

Assignees

• Academisch Ziekenhuis Leiden

Inventors

• Van Der Veer Eric Peter
• Van Zonneveld Anton Jan
• Prins Jurriën

Classifications

• C12N2320/33

  Alteration of splicing · CPC title

• C12N2310/346

  having a combination of backbone and sugar modifications · CPC title

• C12N2310/321

  2'-O-R Modification · CPC title

• C12N2310/315

  Phosphorothioates · CPC title

• C12N2310/11

  Antisense · CPC title