# US 11,433,089 B2 · Blood-brain barrier permeable heteroduplex nucleic acid

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 11,433,089 B2
- Document ID: US11433089B2
- Status: Granted
- Kind: B2
- Application number: 16/335,017
- Filed: 2017-09-25
- Published: 2019-08-15
- Granted: 2022-09-06
- Earliest claimed: 2016-09-23
- Assignees: National University Corporation Tokyo Medical and Dental University
- Applicants: National University Corporation Tokyo Medical and Dental University
- Inventors: Takanori Yokota; Tetsuya Nagata
- Web page: https://patentgrep.com/patent/US11433089B2

## CPC

- A61K 31/711: Natural deoxyribonucleic acids, i.e. containing only 2'-deoxyriboses attached to adenine, guanine, cytosine or thymine and having 3'-5' phosphodiester links
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 31/7088: Compounds having three or more nucleosides or nucleotides
- A61K 31/7125: Nucleic acids or oligonucleotides having modified internucleoside linkage, i.e. other than 3'-5' phosphodiesters
- A61K 47/22: Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
- A61K 47/28: Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
- A61K 47/542: {Carboxylic acids, e.g. a fatty acid or an amino acid}
- A61K 47/554: {the modifying agent being a steroid plant sterol, glycyrrhetic acid, enoxolone or bile acid}
- A61K 48/00: Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 27/02: Ophthalmic agents
- C12N 15/09: Recombinant DNA-technology
- C12N 15/111: {General methods applicable to biologically active non-coding nucleic acids}
- 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)}
- C12N 2310/14: interfering nucleic acids [NA]
- C12N 2310/315: Phosphorothioates
- C12N 2310/321: 2'-O-R Modification
- 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 2310/345: having at least two different backbone modifications
- C12N 2310/346: having a combination of backbone and sugar modifications
- C12N 2310/3515: Lipophilic moiety, e.g. cholesterol
- C12N 2320/32: Special delivery means, e.g. tissue-specific
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

The present invention provides a composition and a method for efficiently delivering a nucleic acid agent to the central nervous system and/or the retina and bringing about antisense effects. Provided is a composition for reducing the expression level of a target transcription product in the central nervous system and/or retina of a subject, the composition including a nucleic acid complex that includes a first nucleic acid strand and a second nucleic acid strand, wherein: the first nucleic acid strand comprises a base sequence capable of hybridizing with at least part of the target transcription product and has an antisense effect on the target transcription product; the second nucleic acid strand comprises a base sequence complementary to the first nucleic acid strand and is conjugated to tocopherol, cholesterol, or an analog thereof; and the first nucleic acid strand is annealed to the second nucleic acid strand.

## Claims

### Claim 1

A method for treating a central nervous system disease of a subject by reducing the expression level of a target transcription product in the central nervous system of the subject, comprising intravenously or subcutaneously administering to the subject a double-stranded nucleic acid agent consisting of a first nucleic acid strand and a second nucleic acid strand,
wherein the first nucleic acid strand comprises a base sequence capable of hybridizing with at least part of the target transcription product and has an antisense effect on the target transcription product;
wherein the second nucleic acid strand comprises a base sequence complementary to the first nucleic acid strand and is conjugated to a tocopherol, cholesterol, or an analog thereof;
wherein the first nucleic acid strand is annealed to the second nucleic acid strand;
wherein the first nucleic acid strand is a gapmer or a mixmer, and
wherein the subject has a central nervous system disease.

### Claim 2 (depends on 1)

The method according to claim 1, wherein the first nucleic acid strand comprises at least four consecutive deoxyribonucleosides.

### Claim 3 (depends on 2)

The method according to claim 2, wherein the second nucleic acid strand comprises at least four consecutive ribonucleosides complementary to the at least four consecutive deoxyribonucleosides in the first nucleic acid strand.

### Claim 4 (depends on 1)

The method according to claim 1, wherein the first nucleic acid strand is 13 to 20 bases in length.

### Claim 5 (depends on 1)

The method according to claim 1, wherein the central nervous system is selected from the group consisting of cerebral cortex, basal ganglion, cerebral white matter, diencephalon, brainstem, cerebellum, and spinal cord.

### Claim 6 (depends on 1)

The method according to claim 1, wherein the central nervous system is selected from the group consisting of frontal lobe, temporal lobe, hippocampus, parahippocampal gyms, parietal lobe, occipital lobe, striatum, globus pallidus, claustrum, thalamus, subthalamic nucleus, midbrain, substantia nigra, pons, medulla oblongata, cerebellar cortex, cerebellar nucleus, cervical spinal cord, thoracic spinal cord, and lumbar spinal cord.

### Claim 7 (depends on 1)

The method according to claim 1, wherein the double-stranded nucleic acid agent is administered at 5 mg/kg or more per dose.

### Claim 8 (depends on 1)

The method according to claim 1, wherein the second nucleic acid strand does not comprise natural ribonucleosides.

### Claim 9 (depends on 1)

The method according to claim 1, wherein the nucleic acid portion of the second nucleic acid strand consists of deoxyribonucleosides and/or sugar-modified nucleosides, wherein the deoxyribonucleosides and/or sugar-modified nucleosides are linked by a modified or unmodified internucleoside linkage.

### Claim 10 (depends on 1)

The method according to claim 1, wherein a ligand is conjugated to the second nucleic acid strand via an uncleavable linker.

### Claim 11 (depends on 1)

The method according to claim 1, wherein the double-stranded nucleic acid agent permeates the blood brain barrier (BBB).

### Claim 12 (depends on 1)

The method according to claim 1, wherein the second nucleic acid is conjugated to a tocopherol.