Oligonucleotide therapy for Wilson disease
Inventors
Merico, Daniele • Wienholds, Erno • SCHMITGES, Frank • O'Hara, Matthew
Assignees
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Publication Number
US-11578327-B2
Publication Date
2023-02-14
Expiration Date
Abstract
The present disclosure provides antisense oligonucleotides, compositions, and methods that target ATP7B exon 6 or a flanking intron, thereby modulating splicing of ATP7B pre-mRNA to increase the level of ATP7B mRNA molecules having exon 6, e.g., to provide a therapy for Wilson disease. The present disclosure provides an antisense oligonucleotide including a nucleobase sequence at least 70% complementary to an ATP7B target sequence in exon 6, a 5′-flanking intron, a 3′-flanking intron, or a combination of exon 6 and the 5′-flanking or 3′-flanking intron.
Core Innovation
The invention provides antisense oligonucleotide therapies for Wilson disease by modulating splicing of ATP7B pre-mRNA. The antisense oligonucleotide targets ATP7B exon 6 and/or adjacent 5′-flanking intron and 3′-flanking intron splicing regulatory elements, with the aim of increasing exon 6 inclusion in ATP7B pre-mRNA.
The invention specifies antisense oligonucleotide target selection using nucleobase complementarity to an ATP7B pre-mRNA target sequence spanning exon 6 and/or the 5′- or 3′-flanking intron. The disclosed rationale states that binding of the antisense oligonucleotide reduces splicing factor binding to intronic splicing silencers.
The invention further defines antisense oligonucleotide compositions and chemistry options, including nucleobase modifications, modified internucleoside linkages, and modified sugar nucleosides, as well as morpholino oligomers. The disclosed pharmaceutical compositions include administration to subjects to increase exon 6-containing ATP7B mRNA and thereby treat Wilson disease.
Claims Coverage
The independent claim covers antisense oligonucleotides with defined length, complementarity constraints to an ATP7B pre-mRNA target sequence in exon 6 and/or adjacent introns, and specified target region and sequence identity limitations. The claim also permits multiple modified oligonucleotide chemistries, including morpholino oligomers.
Complementary antisense targeting of ATP7B pre-mRNA in exon 6 and/or flanking introns
An antisense oligonucleotide comprising 10 to 50 nucleotides with a nucleobase sequence at least 95% complementary over the entire length to an ATP7B pre-mRNA target sequence in exon 6, a 5′-flanking intron, a 3′-flanking intron, or a combination of exon 6 and the 5′-flanking or 3′-flanking intron.
Modified oligonucleotide chemistry including morpholino oligomers
The antisense oligonucleotide comprises at least one modified nucleobase, at least one modified internucleoside linkage, or at least one modified sugar nucleoside, or is a morpholino oligomer.
Constrained ATP7B target nucleotide positions and terminal complementarity exclusions
The ATP7B target sequence comprises at least one nucleotide located among positions 54672-54680 or 54691-54701 in SEQ ID NO:1, with the 5′-terminal nucleotide complementary to neither position 54695 nor position 54696 of SEQ ID NO:1; and the ATP7B target sequence is located within specified ranges in the 5′-flanking intron, the 5′-flanking intron together with exon 6, and/or specified ranges among positions in SEQ ID NO:1 that include exon 6 and/or the surrounding intron regions.
High identity nucleobase sequences relative to defined SEQ ID NO set
The nucleobase sequence has at least 95% sequence identity to a listed set of SEQ ID NOs.
The claim coverage centers on an antisense oligonucleotide with strong complementarity to an ATP7B pre-mRNA target spanning exon 6 and/or adjacent intron regions, optional modified nucleic-acid chemistry including morpholino oligomers, and constrained target-position and sequence-identity requirements tied to SEQ ID NO:1 and a defined set of SEQ ID NOs.
Stated Advantages
Increases exon 6-containing ATP7B mRNA.
Modulates splicing of ATP7B pre-mRNA to increase exon 6 inclusion.
Treats Wilson disease by administering an antisense oligonucleotide targeting ATP7B exon 6 and/or adjacent intron splicing regulatory elements.
Functional rescue and ATP7B protein level increases are described in documented examples.
Documented Applications
Method embodiments for increasing exon 6-containing ATP7B mRNA.
Therapeutic use for Wilson disease by administering the antisense oligonucleotide to subjects to increase exon 6-containing ATP7B mRNA.
Treatment of subjects with aberrant ATP7B gene variants, including M645R/g.54646T>G, by administering the antisense oligonucleotide.
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