# US 2011/0256156 A1 · TRANSFERRIN/TRANSFERRIN RECEPTOR-MEDIATED siRNA DELIVERY

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- Number: US 2011/0256156 A1
- Document ID: US20110256156A1
- Status: Published application
- Kind: A1
- Application number: 13/112,635
- Filed: 2011-05-20
- Published: 2011-10-20
- Earliest claimed: 2007-10-03
- Assignees: Alcon Research, Ltd.
- Inventors: Jon E. Chatterton; Abbot F. Clark
- Web page: https://patentgrep.com/patent/US20110256156A1

## 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)}
- A61K 9/0048: {Eye, e.g. artificial tears}
- A61K 31/7088: Compounds having three or more nucleosides or nucleotides
- A61K 31/713: Double-stranded nucleic acids or oligonucleotides
- A61K 47/64: Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent (peptidic linkers A61K47/65)
- A61K 47/644: {Transferrin, e.g. a lactoferrin or ovotransferrin}
- A61K 47/6849: {the antibody targeting a receptor, a cell surface antigen or a cell surface determinant}
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 27/02: Ophthalmic agents
- A61P 27/06: Antiglaucoma agents or miotics
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- C12N 15/87: Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation
- C12N 2310/14: interfering nucleic acids [NA]
- C12N 2310/141: MicroRNAs, miRNAs
- C12N 2310/3513: Protein; Peptide
- C12N 2320/32: Special delivery means, e.g. tissue-specific
- 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 invention provides interfering RNA molecule-ligand conjugates useful as a delivery system for delivering interfering RNA molecules to a cell in vitro or in vivo. The conjugates comprise a ligand that can bind to a transferrin receptor (TfR). Therapeutic uses for the conjugates are also provided.

## Claims

### Claim 1

A method of delivering an interfering RNA molecule to an eye of a patient, comprising administering to the patient an interfering RNA molecule-ligand conjugate, wherein the ligand can bind to a transferrin receptor (TfR).

### Claim 2 (depends on 1)

The method of claim 1, wherein the ligand comprises a TfR binding domain of transferrin.

### Claim 3 (depends on 2)

The method of claim 2, wherein the ligand comprises the Tf C-lobe or a TfR-binding portion thereof.

### Claim 4 (depends on 1)

The method of claim 1, wherein the ligand comprises a TfR-binding peptide, a TfR-binding aptamer, or a TfR-specific antibody or a fragment thereof.

### Claim 5 (depends on 1)

The method of claim 1, wherein the interfering RNA molecule is linked to the ligand via a nucleic acid binding protein.

### Claim 6 (depends on 1)

The method of claim 1, wherein the interfering RNA molecule is linked to the ligand via a polycation.

### Claim 7 (depends on 1)

The method of claim 1, wherein the interfering RNA molecule is linked to the ligand via a 7×Arg peptide, 8×Arg peptide, 9×Arg peptide, 10×Arg peptide, or 11×Arg peptide.

### Claim 8 (depends on 7)

The method of claim 7, wherein the interfering RNA molecule is linked to the ligand via a 9×Arg peptide.

### Claim 9 (depends on 1)

The method of claim 1, wherein the conjugate comprises an HA2 peptide.

### Claim 10 (depends on 1)

The method of claim 1, wherein the conjugate is administered to the patient in the presence of an HA2 peptide.

### Claim 11 (depends on 1)

The method of claim 1, wherein the interfering RNA molecule is covalently linked to the ligand.

### Claim 12 (depends on 1)

The method of claim 1, wherein the conjugate is administered by intraocular injection, ocular topical application, subconjunctival injection, intravitreal injection, anterior or posterior juxtascleral injection, intravenous injection, oral administration, intramuscular injection, intraperitoneal injection, transdermal application, intranasal application, or transmucosal application.

### Claim 13 (depends on 1)

The method of claim 1, wherein the interfering RNA molecule is a siRNA, miRNA, or shRNA.

### Claim 14

An interfering RNA molecule-ligand conjugate, wherein the ligand can bind to a transferrin receptor (TfR).

### Claim 15 (depends on 14)

The interfering RNA molecule-ligand conjugate of claim 14, wherein the ligand comprises a TfR binding domain of transferrin.

### Claim 16 (depends on 15)

The interfering RNA molecule-ligand conjugate of claim 15, wherein the ligand comprises the Tf C-lobe or a TfR-binding portion thereof.

### Claim 17 (depends on 14)

The interfering RNA molecule-ligand conjugate of claim 14, wherein the ligand comprises a TfR-binding peptide, a TfR-binding aptamer, or a TfR-specific antibody or a fragment thereof.

### Claim 18 (depends on 14)

The interfering RNA molecule-ligand conjugate of claim 14, wherein the interfering RNA molecule is linked to the ligand via a nucleic acid binding protein or a polycation.

### Claim 19 (depends on 14)

The interfering RNA molecule-ligand conjugate of claim 14, wherein the interfering RNA molecule is linked to the ligand via a 7×Arg peptide, 8×Arg peptide, 9×Arg peptide, 10×Arg peptide, or 11×Arg peptide.

### Claim 20 (depends on 19)

The interfering RNA molecule-ligand conjugate of claim 19, wherein the interfering RNA molecule is linked to the ligand via a 9×Arg peptide.

### Claim 21 (depends on 14)

The interfering RNA molecule-ligand conjugate of claim 14, wherein the conjugate comprises an HA2 peptide.

### Claim 22 (depends on 14)

The interfering RNA molecule-ligand conjugate of claim 14, wherein the interfering RNA molecule is a siRNA, miRNA, or shRNA.

### Claim 23 (depends on 14)

A pharmaceutical composition comprising the interfering RNA molecule-ligand conjugate of claim 14.

### Claim 24 (depends on 14)

A method of treating or preventing an ocular disorder in a patient, comprising administering to the patient the interfering RNA molecule-ligand conjugate of claim 14, wherein the interfering RNA molecule can attenuate expression of a gene associated with the ocular disorder.

### Claim 25 (depends on 24)

The method of claim 24, wherein the conjugate is administered by intraocular injection, ocular topical application, subconjunctival injection, intravitreal injection, anterior or posterior juxtascleral injection, intravenous injection, oral administration, intramuscular injection, intraperitoneal injection, transdermal application, intranasal application, or transmucosal application.

### Claim 26 (depends on 24)

The method of claim 24, wherein the conjugate is administered to the patient in the presence of an HA2 peptide.

### Claim 27 (depends on 24)

The method of claim 24, wherein the ocular disorder is associated with ocular angiogenesis, dry eye, ocular inflammatory conditions, ocular hypertension, or glaucoma.