# US 12,180,480 B2 · Angelman syndrome antisense treatment

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- Number: US 12,180,480 B2
- Document ID: US12180480B2
- Status: Granted
- Kind: B2
- Application number: 18/345,452
- Filed: 2023-06-30
- Published: 2023-10-19
- Granted: 2024-12-31
- Earliest claimed: 2017-12-01
- Assignees: The Texas A&M University System
- Applicants: The Texas A&M University System
- Inventors: Scott Victor Dindot
- Web page: https://patentgrep.com/patent/US12180480B2

## CPC

- C12N 15/113: Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; {Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing (when used in plants C12N15/8218)}
- C07H 21/00: Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
- C07H 21/02: with ribosyl as saccharide radical
- C07H 21/04: with deoxyribosyl as saccharide radical
- C12N 2310/113: targeting other non-coding nucleic acids, e.g. antagomirs
- C12N 2310/315: Phosphorothioates
- C12N 2310/3231: having an additional ring, e.g. LNA, ENA
- C12N 2310/3341: 5-Methylcytosine
- C12N 2310/341: Gapmers, i.e. of the type ===---===
- C12N 2310/346: having a combination of backbone and sugar modifications
- C12N 2320/30: Special therapeutic applications
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- C07H: SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS (derivatives of aldonic or saccharic acids C07C, C07D; aldonic acids, saccharic acids C07C59/105, C07C59/285; cyanohydrins C07C255/16; glycals C07D; compounds of unknown constitution C07G; polysaccharides, derivatives thereof C08B; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; sugar industry C13)

## Abstract

Disclosed herein are antisense 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 at the 5′-end of UBE3A-AS, which is downstream of SNORD115-45 snoRNA. Also disclosed are pharmaceutical compositions and methods for treatment of Angelman syndrome.

## Claims

### Claim 1

A modified oligonucleotide comprising a contiguous nucleotide sequence of 13 to 30 nucleotides in length with nucleic acid complementarity to a contiguous portion of the nucleotide sequence set forth in SEQ ID NO: 2, wherein the modified oligonucleotide comprises from 5′ to 3′ (a) a first segment comprising 3-5 modified ribonucleotides, (b) a second segment comprising at least 7 deoxyribonucleotides, and (c) a third segment comprising 3-5 modified ribonucleotides.

### Claim 2 (depends on 1)

The modified oligonucleotide of claim 1, comprising a sequence having nucleic acid sequence complementarity to a nucleotide sequence selected from the group consisting of SEQ ID NOs: 18 to 66.

### Claim 3 (depends on 1)

The modified oligonucleotide of claim 1, comprising a sequence selected from the group consisting of SEQ ID NO: 67 to 115.

### Claim 4 (depends on 1)

The modified oligonucleotide of claim 1, wherein the modified ribonucleotides of the first segment or the third segment are independently selected from the group consisting of 2-O-alkyl-RNA, 2′-O-methyl-RNA, 2′-alkoxy-RNA, 2-O-methoxyethyl-RNA, 2′-amino-DNA, 2′fluoro-DNA, arabino nucleic acid (ANA), 2-fluoro-ANA, and locked nucleic acid (LNA) nucleoside.

### Claim 5 (depends on 1)

The modified oligonucleotide of claim 1, comprising at least one modified internucleoside linkage.

### Claim 6 (depends on 5)

The modified oligonucleotide of claim 5, wherein the at least one modified internucleoside linkage comprises a phosphorothioate internucleoside linkage.

### Claim 7 (depends on 6)

The modified oligonucleotide of claim 6, wherein the modified oligonucleotide is fully phosphorothioate-modified.

### Claim 8 (depends on 1)

The modified oligonucleotide of claim 1, wherein the modified oligonucleotide targets the 5′ end of UBE3A-AS transcript and increases UBE3A expression in a target cell.

### Claim 9 (depends on 1)

The modified oligonucleotide of claim 1, wherein the modified oligonucleotide is conjugated to one or more non-nucleotide moiety.

### Claim 10 (depends on 9)

The modified oligonucleotide of claim 9, wherein the one or more non-nucleotide moiety is selected from the group consisting of carbohydrates, cell surface receptor ligands, drug substances, hormones, lipophilic substances, polymers, proteins, peptides, toxins, vitamins, and viral proteins.

### Claim 11 (depends on 10)

The modified oligonucleotide of claim 10, wherein the non-nucleotide moiety is an antibody or antibody fragment.

### Claim 12 (depends on 11)

The modified oligonucleotide of claim 11, wherein the antibody or antibody fragment facilitates delivery across the blood-brain-barrier.

### Claim 13 (depends on 12)

The modified oligonucleotide of claim 12, wherein the antibody of or antibody fragment targets the transferrin receptor.