# US 2014/0194489 A1 · Compositions and methods for inhibiting expression of tmprss6 gene

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- Number: US 2014/0194489 A1
- Document ID: US20140194489A1
- Status: Published application
- Kind: A1
- Application number: 14/007,835
- Filed: 2012-03-28
- Published: 2014-07-10
- Earliest claimed: 2011-03-29
- Assignees: Alnylam Pharmaceuticals, Inc.
- Inventors: David Bumcrot; Brian Bettencourt; Ivanka Toudjarska
- Web page: https://patentgrep.com/patent/US20140194489A1

## CPC

- C12N 15/1138: {against receptors or cell surface proteins}
- A61K 31/713: Double-stranded nucleic acids or oligonucleotides
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/12: for electrolyte homeostasis
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 7/06: Antianaemics
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C12N 15/1137: {against enzymes (viral enzymes C12N15/1131; receptors C12N15/1138)}
- C12Y 304/21: Serine endopeptidases (3.4.21)
- C12N 2310/14: interfering nucleic acids [NA]
- C12N 2310/315: Phosphorothioates
- C12N 2310/321: 2'-O-R Modification
- C12N 2310/344: Position-specific modifications, e.g. on every purine, at the 3'-end
- C12N 2310/346: having a combination of backbone and sugar modifications
- C12N 2310/351: Conjugate
- 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)
- 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
- C12Y: ENZYMES

## Abstract

The invention relates to double-stranded ribonucleic acid (dsRNA) compositions targeting the TMPRSS6 gene, and methods of using such dsRNA compositions to inhibit expression of TMPRSS6.

## Claims

### Claim 1

A double-stranded ribonucleic acid (dsRNA) for inhibiting expression of TMPRSS6, wherein said dsRNA comprises a sense strand and an antisense strand, the antisense strand comprising a region of complementarity to a TMPRSS6 transcript which comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from one of the antisense sequences listed in Tables 2, 3 or 4.

### Claim 2 (depends on 1)

The dsRNA of claim 1, wherein said dsRNA comprises at least one modified nucleotide.

### Claim 3 (depends on 2)

The dsRNA of claim 2, wherein at least one of said modified nucleotides is chosen from the group consisting of: a 2′-O-methyl modified nucleotide, a nucleotide comprising a 5′-phosphorothioate group, and a terminal nucleotide linked to a cholesteryl derivative or dodecanoic acid bisdecylamide group.

### Claim 4 (depends on 2)

The dsRNA of claim 2, wherein said modified nucleotide is chosen from the group consisting of: a 2′-deoxy-2′-fluoro modified nucleotide, a 2′-deoxy-modified nucleotide, a locked nucleotide, an abasic nucleotide, 2′-amino-modified nucleotide, 2′-alkyl-modified nucleotide, morpholino nucleotide, a phosphoramidate, and a non-natural base comprising nucleotide.

### Claim 5 (depends on 1)

The dsRNA of claim 1, wherein the region of complementarity is at least 17 nucleotides in length.

### Claim 6 (depends on 1)

The dsRNA of claim 1, wherein the region of complementarity is between 19 and 21 nucleotides in length.

### Claim 7

(canceled)

### Claim 8 (depends on 1)

The dsRNA of claim 1, wherein each strand is no more than 30 nucleotides in length.

### Claim 9 (depends on 1)

The dsRNA of claim 1, wherein at least one strand comprises a 3′ overhang of at least 1 nucleotide or at least 2 nucleotides.

### Claim 10

(canceled)

### Claim 11 (depends on 1)

The dsRNA of claim 1, further comprising a ligand.

### Claim 12 (depends on 11)

The dsRNA of claim 11, wherein the ligand is conjugated to the 3′ end of the sense strand of the dsRNA.

### Claim 13 (depends on 1)

The dsRNA of claim 1, wherein the region of complementarity consists of one of the antisense sequences of Tables 2, 3 or 4.

### Claim 14 (depends on 1)

The dsRNA of claim 1, wherein the dsRNA comprises a sense strand consisting of a sense strand sequence selected from Tables 2, 3 or 4 and an antisense strand consisting of an antisense sequence selected from Tables 2, 3 or 4.

### Claim 15 (depends on 1)

A cell containing the dsRNA of claim 1.

### Claim 16 (depends on 1)

A pharmaceutical composition for inhibiting expression of a TMPRSS6 gene comprising the dsRNA of claim 1.

### Claim 17 (depends on 16)

The pharmaceutical composition of claim 16, further comprising a lipid formulation.

### Claim 18

(canceled)

### Claim 19 (depends on 1)

A method of inhibiting TMPRSS6 expression in a cell, the method comprising:
(a) introducing into the cell the dsRNA of claim 1; and
(b) maintaining the cell produced in step (a) for a time sufficient to obtain degradation of the mRNA transcript of a TMPRSS6 gene, thereby inhibiting expression of the TMPRSS6 gene in the cell.

### Claim 20 (depends on 19)

The method of claim 19, wherein the TMPRSS6 expression is inhibited by at least 30%.

### Claim 21 (depends on 1)

A method of treating a disorder mediated by TMPRSS6 expression comprising administering to a human in need of such treatment a therapeutically effective amount of the dsRNA of claim 1.

### Claim 22 (depends on 21)

The method of claim 21, wherein the human has a disorder associated with hemochromatosis, a β-thalassemia, or β-thalassemia intermedia.

### Claim at position 23

23-24. (canceled)

### Claim 25 (depends on 21)

The method of claim 21, wherein the human has a β-thalassemia and wherein the administration of the dsRNA to the subject causes a decrease in iron in the serum of the subject by at least 10%.

### Claim 26 (depends on 21)

The method of claim 21, wherein the dsRNA is administered at a concentration of 0.01 mg/kg-5 mg/kg bodyweight of the subject.

### Claim 27 (depends on 1)

A vector encoding at least one strand of the dsRNA of claim 1, wherein said dsRNA comprises a region of complementarity to at least a part of an mRNA encoding TMPRSS6, wherein said dsRNA is 30 base pairs or less in length, and wherein said dsRNA targets said mRNA for cleavage.

### Claim at position 27

28-29. (canceled)

### Claim 30 (depends on 27)

A cell comprising the vector of claim 27.

### Claim 31 (depends on 1)

The dsRNA of claim 1, wherein the dsRNA comprises a sense strand consisting of a sequence selected from the group consisting of SEQ ID NO:111, SEQ ID NO:455, SEQ ID NO:109, SEQ ID NO:524, SEQ ID NO:89, SEQ ID NO:494, SEQ ID NO:445, SEQ ID NO:592, SEQ ID NO:47, and SEQ ID NO:540; and an antisense strand consisting of a sequence selected from the group consisting of SEQ ID NO:112, SEQ ID NO:456, SEQ ID NO:110, SEQ ID NO:525, SEQ ID NO:90, SEQ ID NO:495, SEQ ID NO:446, SEQ ID NO:593, SEQ ID NO:48 and SEQ ID NO:541.