# US 9,752,152 B2 · Organic compositions to treat beta-ENaC-related diseases

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- Number: US 9,752,152 B2
- Document ID: US9752152B2
- Status: Granted
- Kind: B2
- Application number: 15/166,576
- Filed: 2016-05-27
- Published: 2016-09-22
- Granted: 2017-09-05
- Earliest claimed: 2010-04-23
- Assignees: Arrowhead Pharmaceuticals, Inc.
- Applicants: Arrowhead Pharmaceuticals, Inc.
- Inventors: Antonin De Fougerolles; John Diener; Emma Hickman; Gregory Hinkle; Stuart Milstein; Anne-Marie Pulichino; Andrew Griffin Sprague
- Web page: https://patentgrep.com/patent/US9752152B2

## CPC

- C12N 15/1138: {against receptors or cell surface proteins}
- A61K 31/713: Double-stranded nucleic acids or oligonucleotides
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/18: for pancreatic disorders, e.g. pancreatic enzymes
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/12: for electrolyte homeostasis
- A61P 5/40: Mineralocorticosteroids, e.g. aldosterone; Drugs increasing or potentiating the activity of mineralocorticosteroids
- A61P 5/42: for decreasing, blocking or antagonising the activity of mineralocorticosteroids
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/12: Antihypertensives
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 13/12: of the kidneys
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 39/02: Antidotes
- A61P 41/00: Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C12N 2310/111: spanning the whole gene, or a large part of it
- C12N 2310/14: interfering nucleic acids [NA]
- C12N 2310/31: of the backbone
- C12N 2310/315: Phosphorothioates
- C12N 2310/321: 2'-O-R Modification
- C12N 2310/322: 2'-R Modification
- C12N 2310/344: Position-specific modifications, e.g. on every purine, at the 3'-end
- C12N 2310/351: Conjugate
- C12N 2310/3513: Protein; Peptide
- C12N 2310/3515: Lipophilic moiety, e.g. cholesterol
- C12N 2310/3517: Marker; Tag
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- 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

## Abstract

The present disclosure relates to RNAi agents useful in methods of treating BetaENaC-related diseases such as cystic fibrosis, pseudohypoaldosteronism type 1 (PHA1), Liddle's syndrome, hypertension, alkalosis, hypokalemia, and obesity-associated hypertension, using a therapeutically effective amount of a RNAi agent to Beta-ENaC.

## Claims

### Claim 1

A composition comprising a RNAi agent comprising a first strand and a second strand, wherein: the sequence of the first strand comprises the sequence of GGAUCAUGUGGUCUUGGAA (SEQ ID NO: 124); wherein the length of the first and second strand are each no more than about 30 nucleotides; and wherein the first and/or second strand is modified or unmodified.

### Claim 2 (depends on 1)

The composition of claim 1, wherein the composition further comprises a second RNAi agent to Beta-ENaC.

### Claim 3 (depends on 1)

The composition of claim 1, wherein the RNAi agent comprises at least one modified backbone and/or at least one 2′-modified nucleotide.

### Claim 4 (depends on 1)

The composition of claim 1, wherein the RNAi agent is ligated to one or more agents, wherein the one or more agents are selected from: diagnostic compound, reporter group, cross-linking agent, nuclease-resistance conferring moiety, natural or unusual nucleobase, lipophilic molecule, cholesterol, lipid, lectin, steroid, uvaol, hecigenin, diosgenin, terpene, triterpene, sarsasapogenin, Friedelin, epifriedelanol-derivatized lithocholic acid, vitamin, carbohydrate, dextran, pullulan, chitin, chitosan, synthetic carbohydrate, oligo lactate 15-mer, natural polymer, low- or medium-molecular weight polymer, inulin, cyclodextrin, hyaluronic acid, protein, protein-binding agent, integrin-targeting molecule, polycationic, peptide, polyamine, peptide mimic, and transferrin.

### Claim 5 (depends on 1)

A method of reducing the level and/or expression of Beta-ENaC in an individual, the method comprising the step of administering to the individual a therapeutically effective amount of a composition comprising a pharmaceutically acceptable carrier and the composition of claim 1.

### Claim 6 (depends on 5)

The composition of claim 5, wherein the composition further comprises a second RNAi agent to Beta-ENaC.

### Claim 7 (depends on 5)

The composition of claim 5, wherein the RNAi agent comprises a phosphorothioate and/or a 2′-modified nucleotide.

### Claim 8 (depends on 5)

The composition of claim 5, wherein the RNAi agent is ligated to one or more agents, wherein the one or more agents are selected from: diagnostic compound, reporter group, cross-linking agent, nuclease-resistance conferring moiety, natural or unusual nucleobase, lipophilic molecule, cholesterol, lipid, lectin, steroid, uvaol, hecigenin, diosgenin, terpene, triterpene, sarsasapogenin, Friedelin, epifriedelanol-derivatized lithocholic acid, vitamin, carbohydrate, dextran, pullulan, chitin, chitosan, synthetic carbohydrate, oligo lactate 15-mer, natural polymer, low- or medium-molecular weight polymer, inulin, cyclodextrin, hyaluronic acid, protein, protein-binding agent, integrin-targeting molecule, polycationic, peptide, polyamine, peptide mimic, and transferrin.

### Claim 9 (depends on 1)

The composition of claim 1, wherein the second strand comprises the sequence UUCCAAGACCACAUGAUCC (SEQ ID NO: 123); and wherein the first and/or second strand are modified or unmodified.

### Claim 10 (depends on 9)

The composition of claim 9, wherein the RNAi agent comprises one or more 2′-modifications selected from the group consisting of: 2′-deoxy, 2′-deoxy-2′-fluoro, 2′-O-methyl, 2′-O-methoxyethyl (2′-O-MOE), 2′-O-aminopropyl (2′-O-AP), 2′-O-dimethylaminoethyl (2′-O-DMAOE), 2′-O-dimethylaminopropyl (2′-O-DMAP), 2′-O-dimethylaminoethyloxyethyl (2′-O-DMAEOE), and 2′-O—N-methylacetamido (2′-O-NMA).

### Claim 11 (depends on 9)

The composition of claim 9, wherein the RNAi agent is ligated to one or more agents, wherein the one or more agents are selected from: diagnostic compound, reporter group, cross-linking agent, nuclease-resistance conferring moiety, natural or unusual nucleobase, lipophilic molecule, cholesterol, lipid, lectin, steroid, uvaol, hecigenin, diosgenin, terpene, triterpene, sarsasapogenin, Friedelin, epifriedelanol-derivatized lithocholic acid, vitamin, carbohydrate, dextran, pullulan, chitin, chitosan, synthetic carbohydrate, oligo lactate 15-mer, natural polymer, low- or medium-molecular weight polymer, inulin, cyclodextrin, hyaluronic acid, protein, protein-binding agent, integrin-targeting molecule, polycationic, peptide, polyamine, peptide mimic, and transferrin.

### Claim 12 (depends on 9)

The composition of claim 9, wherein the composition comprises a second RNAi agent targeted to Beta-ENaC.

### Claim 13 (depends on 9)

The composition of claim 9, wherein the RNAi agent comprises a phosphorothioate and/or a 2′-modified nucleotide.

### Claim 14 (depends on 1)

A composition comprising a therapeutically effective amount of a composition of claim 1 and a pharmaceutically acceptable carrier.

### Claim 15 (depends on 9)

A composition comprising a therapeutically effective amount of a composition of claim 9 and a pharmaceutically acceptable carrier.